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Growth Factors and Enzyme-Linked Receptor Signal Systems. Lecture 29BSCI 420/421Nov 8, 2002 “If we have concluded that we are being asked to take senseless risks, then we should no longer accept the counsel of those who tell us that we must fill our world with poisonous chemicals; - PowerPoint PPT Presentation
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Growth Factors and Enzyme-Linked Receptor Signal
SystemsLecture 29 BSCI 420/421 Nov 8, 2002
“If we have concluded that we are being asked to take senseless
risks, then we should no longer accept the counsel of those who
tell us that we must fill our world with poisonous chemicals;
we should look around and see what other course is open to us.”
- Rachel Carson
1. Tyrosine Kinase Receptors2. Proteolysis Signal Pathways3. The NF-kB Pathway
1. Tyrosine Kinase Receptors
Are an important set of signal receptors that are enzymes
They use their own tyrosine kinase activity to initiate a signal
cascade.
I.e., they put a P04= onto specific tyrosines of other proteins.
These usually receive signals that regulate: cell proliferation (growth factors) or cell differentiation (inducers)
There are six major families of receptor tyrosine kinases.All have a TK domain on the cytosolic, COOH-terminal end,A single-pass transmembrane domain, andOne or more cysteine-rich or Ig-like ligand-binding domains.
Mystery: How could binding to the outside of a single-passTM protein turn on an enzyme in the inner (cytosolic) domain?
Most signal mols for these Rec are dimers or polymers.This causes receptor cross linking (in 3 ways):
Allows receptors to cross-phosphorylate each other(autophosphorylation)
Rec cross-P04lationActivates TK activityAnd provides docking sitesFor signal intermediates
Docking of Intracellular Signal moleculesOn P04lated TK
Also, src & Grb can bind by SH2 domains
Ras activation
Discovered In Dros.: Sevenless Drk SOS
The Ras cycle: The 1st member of the small G protein superfamilyAlso Ran, Rab, Rho. Bound to membrane by farnesyl lipid anchor
Downstream of Ras
Raf
Fos/Jun
Erk
Modular organization of signal pathways by protein scaffoldsOr lipid rafts
B-lymphocyte activation by antigen uses PI 3 Kinase & PLC-
The Jak-STAT pathway, activated by -interferon,activates genes that help defend the cell against viruses.
Jak = Janus Kinase after the 2-faced Roman god
Jak/Stat, cont Stat = Signal Transducer & Activator of Transcription
2. Proteolysis Signal Pathways
The Delta/Notch system in Drosophila stimulates differentiation of nerve cells from unspecified epithelial cells.
3. The NFB Pathway E.g. Gene activation by TNF-
Activate steps in immune & inflammatory responses in mammals,
And Dorsal ventral axis determination in insects.