Cinases and Diseases

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Prot in kinas s compris on of th arg st fami i s of vo tionari r at d prot ins and >500 distinct kinas s

ar ncod d b ~2% of a h man g n s1. Kinas s tran-si nt phosphor at sp cificamin acids on ~30% of a h man prot ins, inc ding mo c s that gov rncomp x c ar proc ss s, s ch as growth, diff r ntia-tion, pro if ration and ap pt sis 2. Giv n th importancof th s c ar activiti s, th cata tic activit of kinas sinvo v d in th s pathwa s is string nt r g at d2. Ov rth past 20 ars, m tations in kinas g n s hav b nfo nd to nd r i man h man dis as s, partic ar d v opm nta and m tabo ic disord rs, as w as c r-tain canc rs. Th iso at d nat r and arg vo m of thindivid a g n -mapping st di s has t nd d to imp d

fforts to prod c a compr h nsiv s rv of kinasm tations. How v r, an ov rvi w of kinas m tationsfrom th p rsp ctiv of h man dis as ph not p s co dr v a patt rns of str ct r f nction r ationships that

gov rn d v opm nt and pathog n sis and that co d, int rn, comp m nt xp rim nts fromin vitro and in vivo mod s st ms.

For this R vi w, w hav c rat d inh rit d g rm-in kinas g n m tations b ph not p according to

organ s st m invo v m nt. W a so bri f r vi w thr ationship b tw n kinas g n m tations in somaticc s and canc r ph not p s. W n xt consid r th con-s q nc s of gain- and oss-of-f nction m tations inkinas g n s,genetic plei tr py and l cus heter geneity of c rtain dis as ph not p s. Th ana sis of th distrib -tion of m tations has h p d to d fin cr cia f nctionadomains of kinas s, mutati nal h tsp ts across th kinas

g n fami and th r vanc of vo tionari m diatin ag -sp cific variations(box 1) . An int grat d nd r-

standing of kinas str ct r and f nction wi improvth diagnosis and prognosis of dis as s that ar r at dto kinas g n variation. B ca s kinas s compris~20% of a p tativ dr g targ ts3, w a so disc ss how d fining ph not p g not p r ationships wi h p thd v opm nt of f t r th rapi s.

Basics of kinase structure and functionKinase structure and classification. Most kinas s, xc d-ing th at pica kinas s, contain a cons rv d cata ticdomain, which transf rs a phosphat from ATP to a tar-g t prot in4. This phosphor ation can mod at nz mactivit or aff ct th int raction of th kinas with itsprot in targ ts4, which in t rn can sp cif th down-str am r spons . R g ator domains ar pr s nt ith rwithin or o tsid th kinas cata tic domain and h p

both to oca iz th kinas and to mod at its activit inr spons to vario s stim i(FIG. 1). Th two main c ass sof kinas ar t rosin kinas s (TKs) and s rin thr oninkinas s (STKs), which phosphor at t rosin and s rinor thr onin r sid s on a s bstrat , r sp ctiv 5. BothTKs and STKs can b m mbran -bo nd and n c ar; inaddition, TKs can b transm mbran r c ptors wh r asSTKs can a so b c top asmic.box 2 shows th div rsf nctions of arch t pa STKs and TKs.

Th cata tic domain of prot in kinas s consists of 250300 amino acids and contains 12 cons rv d s b-domains that fo d into a common cata tic cor str c-t r 5. Th amino-t rmina (N)- ob of th cata tic

*Robarts Research Instituteand Departments of Medicine and Biochemistry,Schulich School of Medicineand Dentistry, University of Western Ontario, London,Ontario N6A 5C1, Canada.Scripps Genomic Medicine,Scripps Research Institute,La Jolla, California92037, USA.Correspondence to R.A.H.e-mail: [email protected] i:10.1038/nrg2707

Amino acidsAmin acids c ntain a

asic amin (NH 2) gr up, anacidic car yl (CooH) gr upand a side chain attached t an

alpha car n at m. The 20amin acids can e classified

ased n the charge f theirside chain, which can e neutraln n-p lar, neutral p lar, acidic

r asic.

ApoptosisThe pr cess f pr grammedcell death that d es n tinv lve the release f harmfulsu stances int the surr undingarea. It has crucial functi n indivisi n and differentiati n yeliminating cells that areunnecessary f r appr priateem ry nic devel pment.

Kinase mutations in human disease:interpreting genotypephenotyperelationshipsPiya Lahiry*, Ali Torkamani , Nicholas J. Schork and Robert A. Hegele*

Abstract | Protein kinases are one of the largest families of evolutionarily related proteinsand comprise one of the most abundant gene families in humans. Here we survey kinase

gene mutations from the perspective of human disease phenotypes and further analysethe structural features of mutant kinases, including mutational hotspots. Our evaluationof the genotypephenotype relationship across 915 human kinase mutations thatunderlie 67 single-gene diseases, mainly inherited developmental and metabolic disordersand also certain cancers enhances our understanding of the role of kinases in development,kinase dysfunction in pathogenesis and kinases as potential targets for therapy.

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20 Macmillan Publishers Limited. All rights reserved10


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Box 1 | Kinase genomic mutation databases and resources

Several genomic databases and web resources were accessed during the preparationof this Review, some of which are described here. The Kinase Sequence Database is acollection of protein kinase sequences grouped into families by the homology of theircatalytic domains. Kinase.com explores the function, evolution and diversity of theprotein kinases that comprise the kinome. The Protein Kinase Resource provides acompendium of information on the protein kinases, including tools for structuraland computational analyses as well as links to related databases. Kinweb provides acomprehensive analysis of the functional domains of each kinase gene product anda collection of conserved sequence elements that have been identified by thecomparative analysis of human kinase genes and their murine counterparts. TheKinase Pathway Database classifies protein kinases and their functions. The COSMIC database contains data on somatic mutations in human cancer, and combines curationof the scientific literature with tumour resequencing data from the Cancer GenomeProject at the Sanger Institute, UK.

The characterization of mutations and naturally occurring genetic mutations thataffect kinase protein structure, function and, ultimately, clinical phenotypic endpointswill be greatly facilitated through several recent genomics initiatives. Large-scalesequencing initiatives, such as The Cancer Genome Atlas and the 1000 GenomesProject will identify hundreds of thousands of coding variations, many of which will berare and many of which will be present in kinases. Although Online MendelianInheritance in Man is not a specific curated resource for kinase gene mutations, it

contains extensive clinical descriptions and mutation lists for many of the disordersdiscussed in this Review. There are also disease- or gene-specific kinase databases,such as the multiple endocrine neoplasia type 2 (MEN2) RET database . Oncemutations have been identified, their functional effects need to be assessed usingmodel organisms, such as transgenic mice, and in vitro functional studies. The abilityto overexpress and inactivate (knockout) genes can be valuable to understand thecomplex changes in phenotype due to genomic alterations. The technology of knockout mice has been such an invaluable tool to study human development that theNational Institutes of Health and the International Knockout Mouse Consortium havecreated a public resource of mouse embryonic stem cells containing null orconditional mutations in every gene in the mouse genome 85. Finally, the recentrestructuring of the Protein Structure Initiative to emphasize biomedical applicationswill enhance the characterization of normal and mutant kinase structures, leading togreater insight into the molecular effects of genetic variations.

Genetic pleiotropyThe effect f a single gene

n multiple phen typic traits.The underlying mechanismis related t the effects

f the gene pr duct nvari us targets.

Locus heterogeneityThis ccurs when a phen typeis caused y mutati ns at m rethan ne gene l cus, whichsuggests that the pr ducts f the genes el ng t the samemeta lic pathway.

Mutational hotspotsA regi n in which the frequency

f mutati n is greater thane pected, wing t specificstructural and/ r functi nalfeatures f the pr tein r gene.

KinomeThe set f pr tein kinases in

the gen me f an rganism.

domain contains a g cin -rich str tch of r sid s(GxGxxG) that is cr cia for ATP binding and phos-phor transf r. B contrast, th C-t rmin s of thcata tic domain is invo v d in s bstrat binding, andth N-t rmin s of this domain contains a cons rv daspartic acid that is important for th cata tic activit of th nz m 5.

Phylogenetic relationships. Th h man kin me can bs bdivid d into s v n ma or gro ps according to ths q nc and str ct r of th cata tic domain1, inc d-ing TK, TKl (t rosin kinas - ik ), STe (homo og sof th ast st ri 7, st ri 11 and st ri 20 kinas s),CK1 (cas in kinas 1), AGC (fami of prot in kinas sA, G and C), CAMKs (ca ci m/ca mod in-d p nd ntprot in kinas s) and th high cons rv d CMGC s b-gro p, which contains GSK3, ClK, c c in-d p nd ntkinas s (CDKs) and mitog n-activat d prot in kinas s(MAPKs). Th CMGC s bgro p contains both MAPKs,which contro c ar proc ss s across a kar o-tic ph a, and a so ss- nd rstood kinas s, s ch as

int stina c kinas (ICK).As ma or kinas gro ps and most kinas fam-

i m mb rs hav a cons rv d str ct r and f nctionthro gho t th vo tion of m tazoans, which inc d

a m tic ar kar ot s, it is not s rprising thth s prot ins ar nd r high s ctiv pr ss r to r sistth acc m ation of variation, s ch that an variationthat ads to th abnorma activation or s ppr ssionof kinas activit wi r s t in s v r ph not pic cons q nc s. How v r, th r is no obvio s r ationshipb tw n th kinas s bgro p and patt rns of dis ass sc ptibi it 6,7.

Human diseases due to germline mutationsCar f ph not pic charact rization which w havca d ph nomic ana sis(REFS 8,9) of pati nts withrar monog nic dis as s can indicat patt rns of organs st m invo v m nt that s gg st th pr s nc of bott -n cks and r d ndanci s in tiss -sp cific kinas f nc-tion and xpr ssion. Th s in vivo patt rns ma in t rns gg st nov bio ogica associations10. As a first st ptowards a c rat d databas of kinas pathies , w havco ct d ph not p and g not p data from 67 kinas -r at d g rm in disord rs in h mans. Th fo owing cri-t ria w r s d to constr ct this ist: STKs and TKs w r

inc d d; th corr sponding kinasopathi s w r d riv dfrom th On in M nd ian Inh ritanc in Man(OMIM)and uniProt databas s; th m tations nd r ing achkinasopath ist d had to hav b n va idat d f nction-a in vitro sing bioch mica assa s orin vivo singind c d m tant anima mod s. An abbr viat d v r-sion of this ist is shown in TAbLE 1 and S pp m ntar information S1 (tab ) shows mor comp t d tai s.

O r s rv fo nd 50 kinas s that nd r i 67 dis-tinct sing -g n c inica ntiti s. Approximat ha f oth s dis as -associat d kinas s w r TKs. Of th 915c rat d dis as -associat d m tations, 77% w r mis-s ns m tations, 19% w r nons ns m tations and 4%w r associat d with a t r d sp icing. Mor than 80% of m tations dir ct aff ct d or ncompass d th cata-

tic domain of th r sp ctiv kinas g n . Virt a aorgan s st ms w r aff ct d b kinas m tations, anda tho gh man disord rs invo v d mor than on tis-s , most kinasopathi s co d b c assifi d accordingto th pr dominant organ invo v m nt. Som i stra-tiv kinasopathi s, which ar gro p d b organ s st minvo v m nt, ar disc ss d b ow.

Kinas signa ing pathwa s can a so b indir ct activat d b m tations in n gativ r g ators or downstr amsigna ing compon nts, s ch as m tations in th prot int rosin phosphatas in Noonan s ndrom 11; how v r,s ch m tationa m chanisms that do not dir ct invo v

kinas g n s wi not b f rth r disc ss d h r .

Neurological disorders . A tosoma r c ssiv kinasm tations ar th pr dominant ca s of disparat n -ro ogica dis as s, which rang from d g n rativ and

nc pha opathic disord rs to pi psi s,myasthenia and ataxia. For xamp , tha cong nita contract rs ndrom t p 2 (lCCS2) is an a tosoma r c ssivn rod g n rativ disord r charact riz d b th d g n-

ration of ant rior horn n rons and oint contract r s12.lCCS2 r s ts from a oss-of-f nction sp icing m tationin ERBB3, which ncod s a m mb r of th pid rmagrowth factor r c ptor (eGFR) fami of r c ptor TKs.

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NATuRe ReVIeWS | Genetics VOluMe 11 | jANuARy 2010 | 61

http://sequoia.ucsf.edu/ksd/http://sequoia.ucsf.edu/ksd/http://kinase.com/http://kinase.com/http://www.nih.go.jp/mirror/Kinaseshttp://www.itb.cnr.it/kinweb/http://kinasedb.ontology.ims.u-tokyo.ac.jp:8081/http://www.sanger.ac.uk/genetics/CGP/cosmic/http://cancergenome.nih.gov/http://www.1000genomes.org/http://www.1000genomes.org/http://www.ncbi.nlm.nih.gov/omim/http://www.ncbi.nlm.nih.gov/omim/http://www.arup.utah.edu/database/MEN2/MEN2_welcome.phphttp://www.arup.utah.edu/database/MEN2/MEN2_welcome.phphttp://www.arup.utah.edu/database/MEN2/MEN2_welcome.phphttp://kb.psi-structuralgenomics.org/http://www.uniprot.org/uniprot/Q9UPZ9http://www.ncbi.nlm.nih.gov/omimhttp://www.uniprot.org/http://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.uniprot.org/http://www.ncbi.nlm.nih.gov/omimhttp://www.uniprot.org/uniprot/Q9UPZ9http://kb.psi-structuralgenomics.org/http://www.arup.utah.edu/database/MEN2/MEN2_welcome.phphttp://www.ncbi.nlm.nih.gov/omim/http://www.ncbi.nlm.nih.gov/omim/http://www.1000genomes.org/http://www.1000genomes.org/http://cancergenome.nih.gov/http://www.sanger.ac.uk/genetics/CGP/cosmic/http://kinasedb.ontology.ims.u-tokyo.ac.jp:8081/http://www.itb.cnr.it/kinweb/http://www.nih.go.jp/mirror/Kinaseshttp://kinase.com/http://sequoia.ucsf.edu/ksd/


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1

G-rich loop

G55N CK92 HxN F108 HRD DFG APE W222 R2802

Catalytic loop

Substrate-binding lobeNucleotide (ATP)-binding lobe

Activation segment C4 loop

3 74 5 E E C 8 G F H I G F H I C

| Figure 1 | G a aly doma o o a d g ubdoma u u a d u o .The subdomains

and functional elements of a generic protein kinase catalytic domain are displayed as a linear ribbon diagram. Blockarrows correspond to -sheets ( 15, 7 and 8), waves correspond to -helices ( C and EI) and intervening linescorrespond to unstructured loops (the elements 6 and D are very short and not depicted in the diagram). The G-richloop is one of the most flexible elements of the protein kinase catalytic core and plays a key part in the phosphoryl-transferreaction. The HxN is a conserved motif in the amino (N)-terminal C4 loop, which serves as a hinge point for a C-helixmovement. The position of the a C-helix varies in response to the activation state of the protein kinase, such that it swingsoutward when the kinase is inactive and inward when the kinase is active. The HRD is a conserved motif that includes aconserved aspartate involved directly in catalysis and a regulatory arginine that coordinates with the phosphorylatedresidue in the activation loop after autophosphorylation. Autophosphorylation governs the activation state of proteinkinases. The DFG is a conserved motif that chelates the magnesium ion involved in catalysis. Movements of this loop arerequired for adoption of the active conformation. Finally, APE is a conserved motif in the C-terminal substrate recognitionpocket of kinases. Conserved functional residues (G55, K92, F108, W222 and R280) or motifs are displayed above theribbon, the numbering corresponds to residues of protein kinase A. Motifs, named according to the amino acids involved,are depicted above the ribbon and functional regions are annotated below the ribbon.

KinasopathyA clinical phen type that iscaused y germline mutati nsin the kinase d main f functi nal pr teins that leadt a l ss- f-functi n rgain- f-functi n f the pr tein.

MyastheniaA general term f r an inheritedneur muscular dis rder

characterized y fluctuatingmuscle weakness andfatigua ility that is ftencaused y ne f several types

f functi nal m lecular defectsat the neur muscular juncti n.

Polycythemia veraA l d dis rder in which the

ne marr w verpr ducesred l d cells (and s metimes

ther l d c mp nents). Theresulting increase in l dvisc sity can lead t healthpr lems, especially enhanced

l d cl tting.

In a s cond xamp , 18 diff r nt miss ns m tationsin PRKCG, which ncod s th STK prot in kinas C,ca s th a tosoma dominant n rod g n rativ dis-ord r spinoc r b ar ataxia t p 14(REF. 13) . PRKCGr q ir s activation b ca ci m and diac g c ro b forphosphor ating s v ra signa ing prot in targ ts14, andPrkcg d fici nc ads to arning d ficits in rod nts15,16.How v r, spinoc r b ar ataxia t p 14 is an xc p-tiona n rod g n rativ kinasopath that aris s from adominant activating m tation. Th fact that most oth rn ro ogica kinasopathi s r s t from homoz go s

oss-of-f nction m tations s gg sts that th s dis as saris from th fai r to adapt to an impair d rath rthan an a gm nt d signa ing n twork.

Skeletal and craniosynostosis disorders. Kinasopathi sthat aff ct th sk ton ar s a ca s d b a tosomadominant gain-of-f nction m tations in TKs. For xam-p , gain-of-f nction m tations that aff ct th fibrob astgrowth factor r c ptor (FGFR) fami nd r i s v rad sp asias that ar charact riz d b th pr mat r f s-ing of sk s t r s in infanc 17. Binding of FGFs toth ir r c ptors norma activat s th TK domain of th FGFR; this is fo ow d b phosphor ation of down-str am signa ing, inc ding th activation of th RAS(a sma GTPas ) and MAPK cascad , which timat

ind c s mitog n sis and diff r ntiation18 (box 2) .In contrast to TK m tations, STK m tations s m to

aff ct bon d v opm nt mor g n ra . For xamp ,miss ns m tations in ACVR1(activin A r c ptor t p 1)hav b n associat d with fibrod sp asia ossificans pro-gr ssiva, which is charact riz d b xt nsiv ossification19 and has a homo ogo s ph not p in a mo s mod 19,20.Activins ar growth and diff r ntiation factors in thtransforming growth factor (TGF)- s p rfami 21.

Th rang of g n s and pr pond ranc of g rm inactivating kinas m tations that r s t in sk ta ph -not p s r inforc s th promin nt ro of kinas s in bond v opm nt and diff r ntiation.

Haematological and vascular disorders. A tho gh th rar a f w g rm in m tations that ca s ha mato ogi-ca dis as (TAbLE 1 and S pp m ntar information S1(tab )), th discov r of somatic m tations inc ding

arg chromosoma r arrang m nts and g n f sionv nts in som ka mias and m opro if rativ

disord rs provid d ar vid nc of th importanc of kinas g n m tations in h man dis as . Th arch t pa

xamp of s ch r arrang m nts is th B c r c pto(BCR) ABLf sion g n that nd r i s chronic m oid

ka mia (CMl ) and ac t mphoc tic ka mia22.Th d monstration that oth r f sion g n s invo vingkinas s nd r i ka mia s gg st d a mor g n raassociation, and has d to th d v opm nt of TK inhi-bition sing ag nts s ch as imatinib 23 as a th rap ticapproach for CMl. Int r sting , th r spons to imatinibis mod at d b th BCRABl g not p of th pati nt23.Anoth r xamp of a kinas f sion g n is a somaticBCRFGFR1 f sion g n that is s n occasiona in pati nts with CMl 24 .

Somatic f sion v nts invo ving th jan s kinasg n JAK2, ETV6 (REFS 25,26) and p ric ntrio ar mat -ria 1 (PCM1)27 ar a so associat d with ka mia, anda somatic miss ns m tation (V617F) in JAK2is s nin a arg proportion of pati nts with p lycythemia vera 28.Int r sting , a JAK2g rm in m tation has r c nt b n

r port d to aff ct dis as s sc ptibi it in primar m -ofibrosis r gard ss of th V617F m tationa stat s29.

G rm in kinas m tations can a so aff ct th h artand b ood v ss s. For xamp , a most 30 m tations inth g n ncoding th STK bon morphog n tic prot inr c ptor t p 2 (BMPR2) ar associat d with a tosomadominant primar p monar h p rt nsion30, imp icat-ing BMPR2 in th d v opm nt of th p monar vas-c at r d to its int raction with c-SRC31. Knocko t of Bmpr2 is mbr onic tha in mic d to ab rrant m so-d rm d v opm nt32. In addition, m tant BMPR2 has aninhibitor ff ct on br ast canc r c s, s gg sting it mab s d as a pot ntia anti-canc r th rap tic ag nt33.

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http://www.ncbi.nlm.nih.gov/gene/5582?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/613?ordinalpos=5&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608232http://www.ncbi.nlm.nih.gov/gene/2260?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/3717?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/659?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/659?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/3717?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/2260?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608232http://www.ncbi.nlm.nih.gov/gene/613?ordinalpos=5&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/5582?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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Immunological disorders. Both a tosoma dominant andr c ssiv m tations imp icat c rtain kinas s in th nor-ma f nction of th imm n s st m34. For xamp , Br tonX- ink d agammag ob ina mia is a s v r imm nod fi-ci nc r s ting from a fai r to prod c mat r B m-phoc t s. A most 150 (most miss ns ) m tations havb n r port d in Br ton t rosin kinas (BTK ), which

ncod s a k r g ator of B c d v opm nt35. BTKint racts with TKs invo v d in B mphoc t signa ingpathwa s36, and mic with a Btkm tation ocat d o tsidth kinas domain fai d to prod c B c s37. F rth rmor ,miss ns m tations in IKBKG nd r i two X- ink d dis-

as s, incontin ntia pigm nti and h pohidrotic ctod r-ma d sp asia with imm n d fici nc , which indicat thimportanc of this STK in both T and B c f nction38.Ikbkg -d fici nt mo s mbr os fai to s rviv d tos v r iv r damag r s ting from xc ssiv apoptosis39.

Endocrine and metabolic disorders. A pr pond rancof a tosoma dominant m tations nd r i s ndo-crin and m tabo ic kinasopathi s, and high ights th

xist nc of g n tic p iotrop . For xamp , FGFR1 isimportant in bon d v opm nt, and a so in gonado-g n sis and r prod ction (REF. 40) (FIG. 2a) . S v ra oss-of-f nction m tations in FGFR1 ar associat d withh pogonadotrophic h pogonadism 40. A so, a m tationin AKT2, which ncod s a biq ito s STK that has ak downstr am f nction in activating th ins in r c p-tor, ca s s a tosoma dominant ins in r sistanc witht p 2 diab t s41, m tabo ic d s ipid mia, ipod stroph and h patic st atosis42. Th s findings, tog th r withcorroborating vid nc in Akt2-knocko t mic 43, indi-cat th c ntra importanc of AKT signa ing to ins ins nsitivit . As high ight d b th xamp of FGFR1, akinas can aff ct diff r nt organs bas d on th m tation

Table 1 | Inherited kinasopathies

G ymbol(OMiM umb )

Lo u D a am (OMiM umb ) MOi

Tyrosine kinases

ALK (105590) 2p23 Neuroblastoma (316014) AD

BTK (300300) Xq21.3q22 Agammaglobulinemia (300300) XL

EFNB1(300035 ) Xq12 Craniofrontonasal syndrome (304110) XL

EIF2AK3(604032) 2p12 WolcottRallison syndrome (226980) AR

ERBB3(190151) 12q13 Lethal congenital contractural syndrome type 2 (607598 ) AR

FGFR1(136350 ) 8p11.2p11.1 Osteoglophonic dysplasia (166250 ), Pfeiffer syndrome (101600) andhypogonadotropic hypogonadism (146110)

AD

FGFR2(176943) 10q26 Pfeiffer syndrome (101600 ), Apert syndrome (101200), Crouzonsyndrome (123500) and lacrimoauriculodentodigital syndrome (149730)

AD

FGFR3(134934) 4p16.3 Achondrodysplasia (100800), thanatophoric dysplasia types 1 and 2(187600 and 187601) and Muenke syndrome (602849)

AD

FLT4 (136352 ) 5q35.3 Hereditary lymphedema type 1A (153100) AD

GRK1(180381) 13q34 Oguchi disease 1 (258100 ) AR

INSR ( 147670) 19p13.2 Insulin-resistant diabetes with acanthosis (610549) and Donahuesyndrome (246200)

AD,AR

JAK3(600173) 19p13.1 Severe combined immunodeficiency (600802) AR

KIT (164920) 4q12 Piebaldism (172800) AD

LTK (151520) 15q15.1q21.1 Systemic lupus erythematosus (152700) AR

MERTK (604705) 2q14.1 Retinitis pigmentosa 38 (268000) AR

MUSK (601296) 9q31.3q32 Myasthenic syndrome (608931) AR

NTRK1(191315) 1q23q24 Congenital insensitivity to pain with anhidrosis (256800) AR

NTRK2(600456) 9q22.1 Early obesity, hyperphagia and developmental delay (600456) AD

PANK2 (606157) 20p13p12.3 Pantothenate kinase-type neurodegeneration (234200) AR

PDGFRA (173490) 4q12 Gastrointestinal stromal tumour (606764) AD

RET (164761) 10q11.2 Multiple endocrine neoplasia type 2B (162300), familial medullarythyroid carcinoma (155240), familial pheochromocytoma (171300) andHirschsprung disease (142623)

AD

RET (164761) 10q11.2 Congenital failure of autonomic control (209880) and renal dysplasia(191830)

ND

ROR2 (602337) 9q22 Robinow syndrome (268310) AR

TEK (600221) 9p21 Cutaneous and mucosal venous malformations (600195) AD

ZAP70 (176947) 2q12 Severe-combined immunodeficiency (T cell-negative) (176947) AR

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http://www.ncbi.nlm.nih.gov/gene/695?ordinalpos=5&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/8517?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/8517?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/695?ordinalpos=5&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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t p . How v r, m tations in c rtain kinas s ma aff ctm tip organs sim tan o s , as s n in th cas s inth fo owing s ction.

Multi-organ disorders. Dis as s invo ving m tiporgans can imp icat a ro for a sing kinas in d v op-m nt across a rang of tiss s. M tations in PRKAR1A in Carn s ndrom show th importanc of thisg n in th h art, ndocrin , c tan o s and n ro-na tiss s(REF. 44) (FIG. 2 ) . A so, th invo v m nt of RPS6KA3 in Coffinlowr s ndrom indicat s itscr cia ro in sk ta , growth and cognitiv d v -opm nt 45. Among oth r STKs, ICK was imp icat d

in ndocrin c r broost od sp asia, a m ti-organn onata tha condition(REF. 46) (FIG. 2 ) . A tho ghICK has a d v opm nta ro across a rang of tiss s,p rhaps ar in d v opm nt b for xt nsiv diff r ntiation of mbr onic g rm a rs, its signa ing pathwa and dir ct int ractions with oth r prot ins hav t to bf charact riz d.

Germline and somatic mutations in cancerProt in kinas s ar th most fr q nt m tat d fami of g n s that contrib t to n op astic ma ignanci s,with an approximat fo rfo d ov rr pr s ntationcompar d with a random s ction of th sam n mb r

Table 1 (cont.) | Inherited kinasopathies

G ymbol(OMiM umb )

Lo u D a am (OMiM umb ) MOi

Serinethreonine kinases

ACVR1(102576) 2q23q24 Fibrodysplasia ossificans progressiva (135100) AD

ACVRL1(601284) 12q13 Hereditary haemorrhagic telangiectasia type 2 (600376) AD

AKT2 ( 164731) 19q13.1q13.2 Atypical lipodystrophy (125853) ADBMPR1B(603248) 4q23q24 Brachydactyly type 2A (112600) AD

BMPR2(600799) 2q33 Primary pulmonary hypertension 1 (178600) AD

BRAF (164757) 7q34 Cardiofaciocutaneous syndrome (115150) AD

CDKL5(300203 ) Xp22 Early infantile epileptic encephalopathy type 2 (300672) XL

CHEK2(604373) 22q12.1 LiFraumeni syndrome 2 (609265) AD

ICK (612325) 6p12.3 Endocrinecerebroosteodysplasia (612651) AR

IKBKG(300248) Xq28 Hypohidrotic ectodermal dysplasia (300291) and incontinentia pigmentitype 2 (308300)

XL

IRAK4(606883) 12q12 Invasive pneumococcal disease (610799) and pyogenic bacterialinfections (607676)

AR

MAPK10(602897) 4q21.3 Epileptic encephalopathy LennoxGaustaut type (606369) AR

MEK1(176872) 15q21 Cardiofaciocutaneous syndrome (115150) AD

MEK2(601263) 7q32 Cardiofaciocutaneous syndrome (115150) AD

PHKA2(306000) Xp22.2p22.1 Glycogen storage disease type 9A (types 1 and 2) (306000) XL

PHKG2 (172471) 16p12.1p11.2 Glycogen storage disease type 9C (172471) AR

PINK1(608309) 1p36 Early-onset Parkinson disease 6 (605909) AR

PRKAR1A (188830)

17q23q24 Primary pigmented nodular adrenocortical disease (610489 ) andCarney complex (160980)

AD

PRKCG(176980) 19q13.4 Spinocerebellar ataxia type 14 (605361) AD

RAF1(164760) 3p25 Noonan syndrome type 5 (611553) and LEOPARD syndrome type 2(611554)

AD

RPS6KA3(300075) Xp22.2p22.1 CoffinLowry syndrome (303600) XL

STK11 (602216) 19p13.3 PeutzJeghers syndrome (175200) AD

TGFBR1(190181) 9q22 LoeysDietz syndrome (types 1A and 2A) (609192 and 608967) AD

TGFBR2(190182) 3p23 LoeysDietz syndrome (types 1B and 2B) (610168 and 610380) AD

TRPM7(605692) 15q21 Amyotrophic lateral sclerosisParkinsonism (105500) ND

WNK4 (601844) 17q21q22 Pseudohypo-aldosteronism type 2 (145260) ADACVR, activin A receptor; AD, autosomal dominant; ALK , anaplastic lymphoma kinase; AR, autosomal recessive; BMPR, bonemorphogenetic protein receptor; BTK , Bruton tyrosine kinase; CDKL5, cyclin-dependent kinase-like 5; EFNB1, ephrin B1;FGFR, fibroblast growth factor receptor; GRK1, G protein-dependent receptor kinase 1; ICK , intestinal cell kinase; INSR, insulinreceptor; JAK3, Janus kinase 3; LTK , leukocyte tyrosine kinase; MAPK10, mitogen-activated protein kinase 10; MOI, mode of inheritance; MUSK , muscle, skeletal, receptor tyrosine kinase; ND, not determined; NTRK, neurotrophic tyrosine kinase receptor;PANK2, pantothenate kinase 2; PDGFRA, platelet-derived growth factor receptor a ; PHK, phosphorylase kinase;ROR2, receptor tyrosine kinase-like orphan receptor 2; TGFBR, transforming growth factor- b receptor; XL, X-linked.

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http://www.ncbi.nlm.nih.gov/gene/5573?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=160980http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=160980http://www.ncbi.nlm.nih.gov/gene/5573?ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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|

822

820

806

129011831191102910571023958979 1159

N C

N C

N C

N C

N C

C

PRKAR1A

3760

ICK

673

Kinase core

a Tyrosine kinases

FGFR3

FGFR1

FGFR2

INSR

13820

Insulin-resistant diabetes with acanthosis nigricansDonahue Donahue Donahue

LADD

Achondrodysplasia

Type I TD

ApertCrouzonPfeiffer

Osteoglophonicdysplasia Hypogonadotropic hypogonadism

IR IR IR IR

17934052164127 622659359474 854937

0

472 617 74854111 157245 268341 478508122 372396

Type I TD

0481 757172233 271344 48751755109 378398 626126

0

b Serinethreonine kinases

478 484514 75448103 255358121 377397 623159247

Carney complex

ECO

24 15318261 132 248 250 371317326 350362

329340

3 284269275 399405310347 576614

N

0

Furin-like cysteine-rich region,growth factor receptor Disulphide bridge Active site

Endothelial growth factorreceptor, L domain

Fibronectin,type III-like Signal peptide

Transmembranedomain Regulatory subunit

cAMP or cGMP-dependentserinethreonine kinase domain Cyclic nucleotide-binding site ATP-binding site or pocket Catalytic domain

Serinethreonine catalytic loop Nuclear localization signal Proline-rich region

Immunoglobulindomain

Point or truncationmutation

M TD1TD1AChTD2 TD2

P CS PA

HH P HHHH HH

Ca

CS CS CS

Figure 2 | G l o o y.Germline point mutations in selectedkinases illustrate genetic pleiotropy. Each disease name is displayed onthe schematic diagram of its corresponding kinase on which pointmutations are depicted with red lines. a | The four examples of tyrosinekinases (TKs) are the three proteins from the fibroblast growthfactor receptor (FGFR) family (FGFR1, FGFR2 and FGFR3) and the insulinreceptor (INSR). Point mutations in the FGFR family are associatedwith craniosynotosis syndromes, as well as osteo- and endocrinedysplasias. INSR mutations are associated with endocrine disorders.

b | cAMP-dependent protein kinase type I- a regulatory subunit (PRKAR1A)and intestinal cell kinase (ICK) are shown as examples of serinethreoninekinases (STKs) that are associated with syndromes according to thelocation of point mutations in conserved regions. A, Apert syndrome;Ach, achondrodysplasia; C, carboxyl-terminus; Ca, Carney complex;CS, Crouzon syndrome; ECO, endocrinecerebroosteodysplasia;HH, hypgonadotropic hypogonadism; LADD, lacrimoauriculodentodigitalsyndrome; M, Muenke syndrome; N, amino-terminus; P, Pfeiffer syndrome;TD1, thanatophoric dysplasia type 1; TD2, TD type 2.

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Tumour suppressorA m lecule that inhi itsunc ntr lled cell gr wth such

that its l ss- r reducti n- f-functi n mutati n fav urs thef rmati n f tum urs.

Proto-oncogeneA gene that pr m tes thespecializati n and divisi n f cells; h wever, when it ismutated r e pressed at highlevels, it causes a n rmalcellular gr wth.

NeuroblastomaA childh d cancer derivedfr m immature neur ns f thesympathetic nerv us system.

of g n s47. Som ov rr pr s ntation of kinas s might battrib tab to asc rtainm nt bias, giv n th arg sizof this prot in fami . How v r, m tations in most pro-t in kinas s w r id ntifi d thro gh positiona c oningapproach s, so asc rtainm nt bias is n ik to com-p t acco nt for th ir ov rr pr s ntation amongcanc r g n s47.

Kinases as tumour suppressors or proto-oncogenes .Prot in kinas s ma act as tum ur suppress rs orpr t - nc genes in norma , h a th c s. Th r for , m ta-tions in prot in kinas s ma ad to t morig n sis thro ghn m ro s m chanisms, inc ding th activation of pro if rativ pathwa s, g nomic instabi it , r d ctionof th DNA damag r spons , d activation of apop-totic pathwa s and/or th promotion of angiog n sisand c moti it . As m ntion d abov , s v ra somaticchromosoma trans ocations ma a so ad to consti-t tiv kinas activation, b t th s wi not b f rth rconsid r d h r .

TAbLE 2 provid s xamp s of kinas s that ca s

canc rs d to somatic m tations, main from thCata og of Somatic M tations in Canc r(COSMIC)databas (REF. 48) (box 1) . Th kinas s in this tab havm tations in 1% of samp s ana s d and hav b nf nctiona va at d in m rin mod s (a mord tai d ist of kinas s is provid d inS pp m ntar information S2 (tab )).TAbLE 2 and S pp m ntar info-rmation S2 (tab ) indicat that man canc rs ar dto acq ir d somatic m tations and that most kinas sar proto-oncog n s that d v op th s canc r-ca singsomatic m tations. How v r, som canc r s ndrom sar ca s d b inh rit d g rm in m tations in bothproto-oncog n s and t mo r s ppr ssor g n s(TAbLE 1) .examp s of canc rs ca s d b inh rit d m tations inkinas proto-oncog n s inc d m tip ndocrinn op asia t p 2, th roid carcinoma, ph ochromoc -toma d to RET (th r arrang d d ring transf ctiong n ) m tations, h r ditar gastroint stina stromat mo rs d to p at t-d riv d growth factor r c p-tor (PDGFRA)21 m tations and liFra m ni s n-drom d to CHEK2 (REF. 49) m tations. examp s of t mo r s ppr ssor g n s that ad to canc r d to bothsomatic and g rm in m tations ar MAPK10in braint mo rs and STK11in P tzj gh rs s ndrom .

Structurefunction relationships. Th ro of sp cifickinas str ct ra m tations in both inh rit d canc rs

and thos acq ir d thro gh somatic m tations is s nin neur last ma 50. N rob astoma is a d vastating chi d-hood canc r that has a ow s rviva rat . Both g rm inand somatic m tations in anap astic mphoma r c p-tor t rosin kinas ( ALK ) hav b n id ntifi d in n -rob astoma pati nts5053, high ighting th ro of bothg rm in and somatic m tations of proto-oncog n s int morig n sis. Moss et al. xamin d th distrib tion of th vario s m tations that hav b n id ntifi d ov r thAlK prot in str ct r and inf rr d that most of th m tations w r ik to b activating50. In vitro cgrowth assa s v rifi d th growth advantag of th activating m tations s ch that in c in s that contain d

ith r AlK amp ification or AlK m tation, growthr d ction occ rr d wh n v s of AlK w r r d c db siRNA50.

Sp cific ma ignanci s m diat d b prot in kinas shav b n st di d xt nsiv to id ntif th f nctionaro s and tiss sp cificiti s of th r sponsib kinas . For

xamp , th primar FlT3-bas d ma ignanc is All54.This corr at s with th obs rvation that FlT3 is main fo nd in norma ha matopoi tic c s55. B contrast,r c ptor t rosin kinas - ik orphan r c ptor 2 (ROR2)-bas d canc rs, s ch as r na c and co or cta -sp cifcarcinoma 21,56, invo v tiss s in which ROR2 was notorigina id ntifi d that is, in th chondroc t in-

ag , t nc ph on, h art and d rmis57. Th r for , asp cific canc r ph not p provid s insight into th bio-

ogica f nctions r g at d b th r sponsib m tant orp rt rb d prot in kinas . Additiona , st d ing prot inkinas s invo v d in partic ar forms of canc r can sh d

ight on th nd r ing patho ogica m chanisms. Forxamp , TeK, which is a TK oca iz d to ndoth ia, has

b n obs rv d to ca s br ast, ovarian and r na canc rs.

This insight into th kinas oca ization patt rn ads tob tt r diagnosis and tr atm nt as th ma ignant trigg ris r cogniz d to i in th ndoth ia c in ag ratthan anoth r tiss in th aff ct d organ.

Genotypephenotype relationships Mode of inheritance in kinasopathies . TAbLE 1 shows apr pond ranc of a tosoma dominant kinas -r at ddisord rs compar d with a tosoma r c ssiv or X chro-mosom - ink d dis as s. Int r sting , most of th dis-ord rs that invo v th n rvo s and imm n s st ms ara tosoma r c ssiv , wh r as most of th disord rs thataff ct th sk ta , ha mato ogica , vasc ar and ndocrin and m tabo ic s st ms ar a tosoma dominant.A tho gh th xp anation for th division of m tationt p s across organ s st ms is not appar nt, it ma br vant that th distrib tion of inh ritanc according toorgan s st m invo v m nt mirrors that s n with m ta-tions in amin A/C (LMNA), which ncod s a str ct ranon-kinas n c ar prot in. N ro ogica aminopathi scan show a tosoma r c ssiv inh ritanc , b t m opa-thi s, cardiom opathi s and ndocrinopathi s t nd toshow a tosoma dominant inh ritanc 58. P rhaps thcorr ation b tw n th distrib tion of ph not p s andth mod of inh ritanc in kinasopathi s as w asin oth r disord rs, s ch as aminopathi s r f ctsth rob stn ss of th signa ing n tworks in th co rs

of norma d v opm nt of partic ar tiss s or organs st ms, ik th n rvo s s st m.

Mutati ons resulting in gain- or loss-of- function. A gain-of-f nction m tation incr as s constit tivkinas activit , som tim s ading to nr strain d c -

ar signa ing and ma trigg r oncog n sis or ca srar inh rit d dominant ph not p s. Conv rs , oss-of-f nction m tations can ad to a oss in c signa -

ing, which can aff ct c growth and tiss or organd v opm nt. This is i strat d b m tations in thproto-oncog n RET , which ncod s a r c ptor TKthat b ongs to th cadh rin s p rfami 59. As ReT is

R E V I E W S


http://www.sanger.ac.uk/genetics/CGP/cosmic/http://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.ncbi.nlm.nih.gov/gene/5979?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/238?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/238?ordinalpos=3&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/5979?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.nature.com/nrg/journal/v11/n1/suppinfo/nrg2707.htmlhttp://www.sanger.ac.uk/genetics/CGP/cosmic/


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Table 2 | Selected kinases associated with cancer and related findings in induced mutant animal models

G n exampl s of somatic mutations associat dwith tumorig n sis*

exampl s of ff cts of g n targ t d l tion in transg nicanimal mod ls

ACVR1 Melanoma Embryonic KO is lethal at E9.5; essential in normal mesoderm formation anddevelopment after gastrulation; conditional KO in the ectoderm causes areduction in lens size due to decreased lens cell proliferation

ALK Ovary, breast and lung cancers, neuroblastomas andglioblastomas

Behavioural and neurochemical alterations, KO viable without anygross alterations

BMPR1B Gastric adenocarcinoma and melanoma Forms intact cartilaginous elements

BMPR2 Inhibitory effect on breast cancer cells bydominant-negative protein

Embryonic KO is lethal, fails to form organized structures and lacks mesoderm

BRAF Widespread with greater incidence in ovary, skin, colonand thyroid cancers and glioblastomas

Midgestation lethality with vascular defects due to endothelial apoptosis

BTK Lung carcinoma Missense mutation leads to failure of mature B lymphocyte production and of immunoglobulin heavy chain rearrangement

CHEK2 Glioblastomas Embryonic stem cells fails to maintain -irradiation-induced arrest in G2 phase

ERBB3 Prostate, bladder and breast cancers and glioblastomas Prenatal lethality due to lack of Schwann cells and precursors

FGFR1 Stem cell leukemia lymphoma (FGFR1ZNF198chimerism), pancreatic adenocarcinomas,

glioblastoma, breast carcinomas and lung cancers

Embryonic KO is embryonic lethal due to lack of embryonic growth andmesodermal patterning; in conditional KO mouse limb development is

affectedFGFR2 Glioblastoma, breast, gastric, lung, ovarian, cervical

and endometrial cancerFull or partial gene KO is embryonic lethal as post-implantation developmentis disrupted

FGFR3 Prostrate and cervical cancer, lung, bladder, upperdigestive tract and intestinal carcinoma and plasmacell myeloma

Embryonic KO has defects in long bones, vertebrae growth and inner-eardevelopment; transgenic mice with a missense mutation have retardedendochondral bone growth

FLT4 Increase in metastasis in adenocarcinoma and lymphnode cancer, glioblastoma, kidney and ovary carcinomaand melanoma

Missense mutation in the catalytic domain leads to chylous ascitesaccumulation and limb swelling

INSR Stomach and skin cancers and glioblastomas andcolorectal cancer

Normal birth but postnatal fatal diabetic ketoacidosis

IRAK4 Prostate cancer Severely impaired interleukin 1 and Toll-like receptor signalling

JAK3 Acute megakaryoblastic leukemia and gastric

adenocarcinoma

Knockout of the catalytic domain leads to reduced number of thymocytes and

severe B cell and T cell lymphopeniaKIT Testicular and ovarian tumours Two mutations cause protein deficiency, which leads to white coat colour,

sterility and anaemia due to migration and/or proliferation failure of stem cellpopulations

MAPK10 Loss of expression in some brain tumours Reduced stress-induced JNK activity; protection from brain injury aftercerebral ischaemia or hypoxia

MERTK Renal, head and neck carcinoma C-terminal truncation of the protein leads to macrophages that are deficientin the clearance of apoptotic thymocytes

MUSK Lung cancer Failure to induce neuromuscular synapse formation

NTRK1 Thyroid carcinoma Sensory and sympathetic neuropathies

NTRK2 Skin and lung cancer Conditional KO in the postnatal forebrain has reduced hippocampal-mediatedlearning and overall synaptic strengthening

PDGFRA Neuroblastoma, stomach, soft tissue, small intestine,lung and gastrointestinal cancer, glioblastoma,melanoma and haematopoietic and lymphoid myeloma

Posterolateral diaphragmatic defects

PINK1 Glioblastoma and ovary carcinoma Impaired mitochondrial function

PRKAR1A Soft tissue myxoma, adrenocortical tumours andthyroid carcinomas

Embryonic KO is lethal due to failure of mesodermal structure development;heterozygous knockout has osteoblast neoplasia, and Schwann cell andthyroid tumours

RAF1 Ovarian and lung adenocarcinoma Cardiac muscle-specific conditional deletion leads to left ventriculardysfunction and heart dilation

RET Lung, ovarian, bladder, large intestinal carcinomas,pheochromocytoma, thyroid tumours andglioblastomas

Severe defects in kidney and enteric nervous system development

ROR2 Renal cell and colorectal carcinoma Perinatal lethal with cardiac septal defects and skeletal defects

R E V I E W S




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Simi ar , th FGFR g n s show p iotrop (FIG. 2) .Gain-of-f nction m tations in th r gion of th imm -nog ob in domain of FGFR1r s t in Pf iff r s ndrom and ost og ophonic d sp asia71, and oss-of-f nctionm tations thro gho t th prot in ca s h pogonado-trophic h pogonadism 40. M tations in th r gion of thimm nog ob in domain of FGFR2 ca s Cro zon72,Pf iff r73 or Ap rt s ndrom s74. M tations thro gh-o t FGFR3 (REF. 18) ca s s ndrom s that rang fromachondrop asia75 and h pochondrop asia with acan-thosis nigricans 76 to thanatophoric d sp asias77, andM nk s ndrom (REF. 78) (FIG. 2a) , which is charact r-iz d b sk and sk ta d sp asia, is fo nd withFGFR3 m tations in th r gion of th imm nog ob in domain.A tho gh th comp t xp anation for s ch p iotropamong FGFR m tations r mains siv , it is ik thatin ach cas a ba anc of factors is invo v d, s ch as thposition of th m tation, its ff ct on cata tic or non-cata tic f nction and th abso t chang in kinasactivit that is impart d b th m tation, a in thcont xt of th g n tic backgro nd of th individ a ,th stag of c ar d v opm nt and th anatomica sit

of th aff ct d tiss (s)79.Th ocation of a m tation in a kinas g n ma

a so d t rmin th s v rit of th s ndrom80 (s thInsights from str ct ra st di s s ction b ow). For

xamp , m tations inPRKAR1A nd r i a rang of dis-as s d p nding on th ocation of th m tation(FIG. 2 ) .

PRKAR1A is a wid xpr ss d STK that binds to cAMPand r g at s cata tic f nction in h art, ndocrin tis-s , skin and n rons. Intronic m tations in PRKAR1A that ca s ab rrant sp icing ar associat d with a sss v r ph not p , primar pigm nt d nod ar adr no-cortica dis as81. Conv rs , m tations in cons rv ddomains of PRKAR1A, s ch as th n c otid -binding

Table 2 (cont.) | Selected kinases associated with cancer and related findings in induced mutant animal models

G exampl s of somatic mutations associat dwith tumorig n sis*

exampl s of ff cts of g n targ t d l tion in transg nicanimal mod ls

RPS6KA3 Prostate cancer, breast cancer, gastric adenocarcinomaand glioblastoma

Progressive osteopenia due to impaired osteoblast and osteoclast function

STK11 Widespread with greater incidence in lung, cervicaland pancreatic cancers and melanoma

Midgestation lethality due to neural tube defects, mesenchymal cell death andvascular abnormalities; heterozygous mice have multiple gastric adenomatous

polypsTEK Breast, ovarian and renal cancer Embryonic lethal due to cardiac dysfunction and vascular haemorrhaging

TGFBR1 TGFBR1*6A/9A polymorphism is associated withincreased risk of breast and ovarian cancer.

Midgestation lethality due to abnormal angiogenesis yet intacthaematopoietic potential in the yolk sac

TGFBR2 Hereditary non-polypopsis colon, oesophageal,stomach and lung cancers and glioblastomas

Embryonic lethality due to defects in yolk sac haematopoiesis andvasculogenesis

TRPM7 Inhibitory on head and neck carcinoma cells whenexpression suppressed; breast, ovary and stomachcancers

Embryonic knockout is lethal; conditional T cell-specific deletion showsdisrupted thymopoiesis

WNK4 Lung and ovarian carcinoma and melanoma Transgenic mouse has hypertension, hyperkalemia, hypercalciuria and markedhyperplasia of the distal convoluted tubule

ZAP70 Lung and head and neck carcinoma Missense mutation in the SH2 domain causes autosomal chronic arthritis*Cancer type listed for all somatic mutations recorded in the COSMIC database for each kinase. Increased kinase expression or function, unless otherwise stated.Germline gene knockout, unless otherwise stated. ACVR1, activin A receptor type 1; ALK , anaplastic lymphoma kinase; BMPR, bone morphogenetic proteinreceptor; BTK , Bruton tyrosine kinase; FGFR, fibroblast growth factor receptor; INSR, insulin receptor; IRAK4, interleukin 1 receptor-associated kinase 4; JAK3, Januskinase 3; KO, knockout; MAPK10, mitogen-activated protein kinase 10; MUSK , muscle, skeletal, receptor tyrosine kinase; NTRK, neurotrophic tyrosine kinasereceptor; PDGFRA, platelet-derived growth factor receptor a ; ROR2, receptor tyrosine kinase-like orphan receptor 2; TGFBR, transforming growth factor- b receptor.

wid xpr ss d and has a cr cia ro in n ra cr stin ag s and r g at s c pro if ration, migration, dif-

f r ntiation and s rviva d ring mbr og n sis59, RET m tations ca s mark d div rs ph not p s d p nd-ing on th ir nat r . Constit tiv ReT activit , d toa gain-of-f nction m tation, ads to vario s t p s of h man canc r, inc ding m tip ndocrin n op asiat p 2B60 and its individ a compon nts, s ch as fami -ia m d ar th roid canc r61 and fami ia ph ochro-moc toma 62. How v r, h man RET oss-of-f nctionm tations and Ret disr ption in mic 63 hav b n asso-ciat d with Hirschspr ng dis as , r na ag n sis64 andc ntra h pov nti ation s ndrom65. Simi ar BRAF ,which ncod s a STK that r g at s th eRK signa -

ing pathwa 66, has div rs ph sio ogica cons q nc sbas d on th m tation t p . Somatic gain-of-f nctionBRAF m tations ar associat d with non-Hodgkin m-phoma, co or cta canc r, ma ignant m anoma, th roidcarcinoma and ng carcinoma 67. B contrast, g rm in

oss-of-f nction m tations in BRAF r s t in cardiofacioc tan o s s ndrom (CFC s ndrom ) s ndromin h mans 68, and Braf -n mic di mid-g station,

indicating a k ro for BRAF in th r g ation of programm d c d ath69.

Genetic pleiotropy. S v ra kinas g n s show p iotrop ,in which s v ra ph not p s r s t from m tations inth sam g n (FIG. 2) . For xamp , m tations in thins in r c ptor (INSR) ca s ith r ins in-r sistantdiab t s m it s with acanthosis nigricans or Donohs ndrom (a so ca d pr cha nism)(FIG. 2a) . Th sph not p s indicat th importanc of INSR in growthand m tabo ism thro gh its abi it to activat th p21Ras pathwa , which in t rn contro s prot in s nth sis,g cog n sis, ipog n sis and apoptosis70.

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http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=101600http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=101600http://www.ncbi.nlm.nih.gov/gene/2263?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/2261?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=115150http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=115150http://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/2261?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/2263?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=101600


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sit or th dim rization and phosphor ation r gions,ad to Carn comp x, a s v r m ti-organ t mo r

disord r 44. A so, as not d abov , p iotrop has b nobs rv d for IKBKG m tations, and X- ink d h po-hidrotic ctod rma d sp asia with imm n d fici nc and incontin ntia pigm nti 38 r s t from m tationsin th IKBKG coding s q nc . How v r, X- ink dh pohidrotic ctod rma d sp asia with imm n d fi-ci nc is mi d r and r s ts from m tations in thcoi d-coi domains, and incontin ntia pigm nti ismor s v r and r s ts from m tations that aff ctprot inprot in int ractions.

Locus heterogeneity. Th sam dis as ph not p cansom tim s r s t from m tations in diff r nt kinasg n s, a ph nom non known as oc s h t rog n it . Thisis obs rv d for CFC s ndrom , ca s d main b gain-of-f nction m tations in on of thr STK g n s BRAF , MEK1and MEK2 which a b ong to th RASMAPK

pathwa (REFS 68,82,83) (box 2) . Th m tations in th sg n s show that activation of th RASMAPK pathwa ,r gard ss of th sp cific m tation, r s ts in th samd v opm nta ph not p , and that m tation in an onof th s thr g n s cannot b r sc d b th pr s rv df nction of th r maining two STK g n s84.

M tations in r at d prot ins can a so r s t in simi-ar ph not p s, as i strat d b th FGFR fami .FGFR2

and FGFR3m tations can ach nd r i Cro zon s n-drom 72,85. In g n ra , m tations inFGFR1and FGFR2 ca s most s ndrom s invo ving cranios nostosis, andth dwarfing s ndrom s ar main associat d withFGFR3 m tations. Ost og ophonic d sp asia is an

ov r ap disord r with sk ta f at r s that ar swith FGFR1, FGFR2 and FGFR3 m tations. It r s tsfrom miss ns m tations in FGFR1 that a t r high cons rv d r sid s in th igand-binding and transm m-bran domains, indicating that this r c ptor is a n gativr g ator of ong-bon growth86.

Insights from structural analysis. Giv n that kinas sar part charact riz d b a niq arra of prot instr ct ra m nts, it is possib to q at som kinasf nctions with partic ar str ct ra f at r s(FIG. 3) .This is c ar from an ass ssm nt of th kinas prot instr ct ra f at r s that ar p rt rb d in diff r nt dis-

as stat s:c mm n neutral mutati ns (FIG. 3a) , inh rit d(that is, cong nita ) g rm in dis as -ca sing m tations(FIG. 3 ) and acq ir d somatic c m tations that ti-mat contrib t to t morig n sis(FIG. 3c) occ p oraff ct diff r nt str ct ra m nts across th prot inkinas cata tic cor .

In g n ra , common n tra m tations t nd toocc p th C-t rmina r gions of th cata tic cor ands bstrat -binding or cata tic r sid s ar avoid d. ThC-t rmina r gion is tho ght to hav a basic str ct raro ; th r for , th amino acids in this r gion ma notb as important for f nction as in oth r r gions of thcata tic cor . B contrast, inh rit d g rm in dis as -ca sing m tations, most of which r s t in oss-of-f nction d v opm nta and/or m tabo ic disord rs,t nd to c st r in r gions of th cata tic cor invo v d inr g ation and s bstrat binding, sp cia r sid s thatparticipat in prot inprot in and all steric interacti ns .Th s g rm in dis as m tations on rar occ p

|

a Mutations in generic kinase structure b Congenital disease-causing mutations c Cancer-associated mutations

Region with functionally insignificantfrequency of mutation

Mutation-rich region Mutation-poor region

Figure 3 | s u u al d bu o o a mu a o . a| The structural distribution of common mutations depictedin a generic kinase structure. b | The structural distribution of congenital disease-causing mutations. | The structuraldistribution of cancer-associated mutations. Green represents regions that have a mutation frequency equivalentto what would be expected at random, blue represents regions statistically devoid of mutations and red depictsregions statistically enriched in mutations. The 5% significance level was determined by the general binomialdistribution based on data obtained from general mutation and genetic variation databases such as dbSNP, OMIM,HGVBase and COSMIC 47,48,50,88,89,93 . Note that regions that are either enriched or devoid of mutations differ acrossthe three mutation types and show minimal overlap.

Common neutral mutation

A n n-syn nym us SNPpresent in at least 1% f thehuman p pulati n that iseither vertly neutral r n tkn wn t influence disease inapprecia le ways.

Allosteric interactionIn an enzyme with at least tw

inding sites (an active site andan ther inding site that indsan all steric effect r), the

inding f an all steric effect ralters the structure f theenzyme and increases rdecreases catalytic activity.

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r gions invo v d in ATP binding or cata sis. A possibxp anation for this obs rvation is simp organism

viabi it : p rt rbations in ATP binding or cata sis ma act as comp t oss-of-f nction m tations and ca s

mbr onic tha it rath r than a dis as ph not p87.From TAbLE 2 , knocko ts of man prot in kinas s r s tin mbr onic or p rinata tha it . Th r for , it s msthat at ast som r sid a f nction of th prot in kinasm st b maintain d to a ow viabi it , a tho gh s v rbio ogica d ficits ma r s t. This r q ir m nt forr sid a f nction ma a so xp ain th dis as p iotrop obs rv d for man prot in kinas s (at ast in th cas sin which p iotrop is not xp ain d b kinas activa-tion v rs s oss-of-f nction m tations): th amo nt of r sid a prot in f nction ma xp ain th s v rit of thdis as ph not p .

B contrast, acq ir d somatic m tations that ca s orcontrib t to canc r t nd to pop at ATP binding andcata tic r sid s. Canc r-ca sing somatic m tations can

ith r activat oncog n s or d activat t mo r s ppr s-sors, as disc ss d bri f abov . Activating m tations

incr as th cata tic activit of th prot in kinas , andth r for t nd to a t r r sid s invo v d in th r g a-tion of cata sis. Conv rs , d activating m tations at

ast in th cont xt of canc r ma not r q ir r sid acata tic f nction, as is th cas for inh rit d g rm indis as m tations. Th r for , th dir ct and comp tinactivation of cata tic f nctions ma b on ha mark f at r of canc r-ca sing acq ir d somatic m tations.

Inherited mutational hotspots. In addition to a morg n ra diff r ntia patt rn in th kinas prot in str c-t ra f at r s associat d with inh rit d and acq ir dsomatic m tations, hotspots in g rm in dis as m ta-tions and somatic canc r m tations hav b n obs rv din prot in kinas s87,88. B ass ssing th fr q nc atwhich dis as -associat d m tations ar fo nd in diff r-

nt kinas str ct ra f at r s, r ationships b tw n sp -cific kinas p rt rbations and dis as s can b obtain d.W and oth rs hav charact riz d sp cific positions inkinas s that s m to harbo r m tations across s v radis as s and canc rs88,89; man of th s m tations pr -s mab ad to activation of th kinas(FIG. 3) , and ass ch ma b s d as targ ts for f t r pharmac ticaint rv ntion90. Man of th s dis as -associat d kinasm tationa hotspots hav a so b n st di d in statisticamod s of oncog n sis91.

Inh rit d dis as m tation hotspots t nd to occ p

r sid s of th cata tic cor that ar sp cific to kar -otic prot in kinas s (ePKs) and ar not obs rv d in

kar otic- ik kinas s (elKs), which ar prokar oticsma -mo c kinas s that fo d into th sam g n-

ra str ct r as ePKs. For xamp , th third g cinof th G- oop (G55), th histidin of th HxN motif (H100), and th p tativ r g ator mo c dockingsit s K92 and F108 (th r sid n mb rs corr spondto prot in kinas A (PKA) r sid s), which cap thC4 r gion, hav b n shown (G55, K92 and H100)or ar ik (F108) to b k p a rs in mov m nts of th C-h ix from th inactiv to activ conformationin ePKs (REF. 87) (FIG. 1). B contrast, th C-h ix is h d in a

constit tiv activ conformation in elKs92. Most dis ashotspot r sid s ar invo v d in th sid -chain n twork form d b th APe motif, W222 and R280, which isa niq f at r of ePKs93. Distant r at d elKs inprokar ot s that phosphor at sma m tabo it s ackth s r sid s94, s gg sting a ro for th ePK-sp cificn twork in s bstrat -binding f nction and a ost ricr g ation. Consist nt with this notion, m tation of thAPe g tamat to sin in int grin- ink d kinas ma r d c s bstrat affinit or, a t rnativ , ma r d caffinit for th associat d kinas that is r sponsib fors bstrat phosphor ation95. lik wis , m tation of tharginin of s bdomain XII in ast PKA was shown toaff ct th binding and r as of prot in s bstrat s96.

F rth rmor , inh rit d dis as hotspots t nd notto invo v ultra-c nserved residues in both ePKs andelKs. Th s r sid s ar ik to b k to kinas cata-

tic activiti s, and va idat th pr vio s obs rvationthat cata tic activit is som what pr s rv d in dis asstat s. Rath r, th kinas str ct ra hotspots associat dwith inh rit d, cong nita dis as s s gg st a ro for th

in ag -sp cific variations that nd r i c rtain bio ogi-ca f nctions in dis as . This in ag -sp cific r g ationis a s condar v of r g ator comp xit a r dtop of th mor anci nt cata tic machin r .

Acquired mutational hotspots. Acq ir d somatic canc r-ca sing kinas m tations a so c st r into str ct rahotspots. Th s hotspots inc d th gatekeeper residue ,r sid s that ar C-t rmina to th DFG motif and r si-d s ad ac nt to th n c otid -binding pock t. Th sr sid s ar k p a rs in ATP binding, cata tic r g ation and, in som cas s, binding of ATP-mim tic dr gs.Th s hotspots t nd to b kinas -activating m tationsas a m ch wid r rang of m tations co d knocko tkinas activit b d stabi izing th str ct r of th pro-t in, wh r as incr asing cata tic activit r q ir s morpr cis fin t ning of th kinas r g ator machin r .

In addition to patt rns in th sp cific kinas r sid sin th cata tic cor that ar p rt rb d in dis as -ca singstat s, th r ar m tationa tr nds invo ving acc ssor domains and sp cific t p s of amino acid s bstit tionsthat probab r f ct mor s bt mo c ar ph sio ogi

ff cts. For xamp , dis as -ca sing m tations in kinasacc ssor domains that inc d r g ator domains, s chas n c ar oca ization signa s and SH2-binding domains,ar d to point m tations in th amino acid s q nc orto sp icing ab rrations in th kinas - ncoding transcript.

Ov ra , o r obs rvations s gg st that transitions from arginin , c st in , g cin , pro in and s rin w r mostcommon s n to nd r i dis as . F rth rmor , transi-tions to arginin , pro in , c st in , histidin and s rinw r most common s n to nd r i dis as , whichs gg sts a f rth r v of comp xit b which kinasm tations icit pathog nic ff cts4,87. Aft r gro pingamino acids according to th po arit and charg of th irsid chain, th most fr q nt amino acid transitionsocc r in th non-po ar gro p, fo ow d b transitions inth po ar gro p in which basic-po ar amino acids ar fr -q nt s bstit t d to n tra -po ar amino acids. Oth rpr va nt int rgro p transitions inc d basic-po ar

Ultra-conserved residueAn amin acid in a pr tein thathas virtually 100% sequenceidentity acr ss many speciesspanning hundreds f milli ns

f years f ev luti n,suggesting that it has s meessential r le(s) in nt genyand devel pment.

Gatekeeper residueA residue in the ATP- indingsite f a pr tein kinase thatc ntr ls the access f ATP rATP-mimetic inhi it rs t the

inding p cket.

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AcknowledgementsP.L. is supported by the Canadian Institutes of HealthResearch (CIHR) Scriver Family M.D./Ph.D. studentship awardand the Heart and Stroke Foundation of Ontario VascularTraining Program. R.A.H. holds the Edith Schulich VinetCanada Research Chair (Tier I) in Human Genetics and theJacob J. Wolfe Distinguished Medical Research Chair. Thiswork was supported by operating grants from the Heart andStroke Foundation of Ontario (NA 6,018), the CanadianInstitutes for Health Research (MOP 13,430 and 79,533),the Jean Davignon Distinguished Cardiovascular-MetabolicResearch Award (Pfizer, Canada) and Genome Canadathrough the Ontario Genomics Institute. N.J.S. and A.T.are supported in part by the Scripps TranslationalScience Institute Clinical Translational Science Award(NIH U54RR02504-01). A.T. is also supported in part by aScripps Dickinson Fellowship. We thank Natarajan Kannan forproviding an earlier version of Figure 1.

Competing interests statementThe authors declare no competing financial interests.

DATABASESEntrez Gene: http://www.ncbi.nlm.nih.gov/gene ALK | BCR| BMPR2 | BRAF | BTK | FGFR1 | FGFR2 | FGFR3 |IKBKG| JAK2| PRKAR1A| PRKCG | RET OMIM: http://www.ncbi.nlm.nih.gov/omimCarney syndrome | CFC syndrome | CML | Pfeiffer syndromeUniProtKB: http://www.uniprot.orgICK

FURTHER INFORMATIONRobert Hegeles homepage: http://www.robarts.ca/hegele1000 Genomes: http://www.1000genomes.orgCatalogue of Somatic Mutations in Cancer (COSMIC): http://www.sanger.ac.uk/genetics/CGP/cosmicKinase.com: http://kinase.comKinase Pathway Database:http://kinasedb.ontology.ims.u-tokyo.ac.jp:8081Kinase Sequence Database: http://sequoia.ucsf.edu/ksd/KinMutBase: http://bioinf.uta.fi/KinMutBaseKinweb Kinase Database: http://www.itb.cnr.it/kinweb or http://kinweb.ceinge.unina.it /Multiple endocrine neoplasia type 2 (MEN2) RET database: http://www.arup.utah.edu/database/MEN2/MEN2_welcome.phpProtein Kinase Resource: http://www.nih.go.jp/mirror/KinasesProtein Structure Initiative :http://kb.psi-structuralgenomics.orgThe Cancer Genome Atlas: http://cancergenome.nih.gov

SUPPLEMENTARY INFORMATIONSee online article: S1 (table) | S2 (table)

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