CHAPTER 5Growth Factors, Receptors, and Cancer

The human EGF receptor (HER) signaling network.

Normal metazoan (後生動物 ) cells control each other’s lives

Maintenance of tissue architecture.

Storage of PDGF by platelets

Effects of growth factors on cells.

The Src protein functions as a tyrosine kinase

Actions of protein kinases

Substrate specificity of the Src kinase

The EGF receptor functions as a tyrosine kinase

Structure of tyrosine kinase receptors

An altered growth factor receptor can function as an oncoprotein

Deregulation of receptor firing

A growth factor gene can become an oncogene: the case of sis

Transphosphorylation underlies the operations of receptor tyrosine kinasesFormation of phosphotyrosine on the EGFR following ligand addition

Apparent autophosphorylation of EGFR

32PO4

Receptor dimerization, ligand binding, transphosphorylation and glioblastoma pathogenesis

Alternative mechanisms of growth factor-induced receptor dimerization.

homodimer

triple

Back-to-back

Gene fusion causing constitutively dimerized receptors

Multiple structural alterations affect Kit receptor firing.

GIST: gastrointestinal stromal tumor

AML: acute myelogenous leukemia

Kit receptor

Yet other types of receptors enable mammalian cells to communicate with their environment

Structure of cytokine receptors.

Structure of the TGF-b receptor

Jaks (Janus kinases)Noncovalently attached

Structure of the Notch receptor

Two successive proteolytic cleavages

The Patched-Smoothened signaling system

Trapping Gli

Canonical Wnt signaling via Frizzled receptors

Non-canonical Wnt signaling via Frizzled receptors

Nuclear receptors sense the presence of low–molecular–weight lipophilic ligands

Steroid sex hormones, retinoids, vitamin D

Estrogen, progesterone and androgen

RXR (retinoid X receptor)PPAR-g (peroxisome proliferator-activated receptor-g)

DES (E2 mimic diethylstibestrol)

Co-activatorsCo-repressors

Extracellular matrixGlycoprotein, hyaluronan and proteoglycans

Integrin receptors sense association between the cell and the extracellular matrix

Mg2+ , Mn2+ , Ca2+

a2b1 integrin- collagen I

Integrin tethering to the ECM and cytoskeleton

Focal adhersionActin fiber

Intermediary protein

Some integrins are essential for tumorigenesis

The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein

The structure of the Ras protein and its response to GTP binding.

Alternative mechanisms of transformation by Ras.

5 min after EGF is added