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; we should look around and see what other course is open to us.” - Rachel Carson 1.Tyrosine Kinase Receptors 2.Proteolysis Signal Pathways 3.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, and One or more cysteine-rich or Ig-like ligand-binding domains.

Mystery: How could binding to the outside of a single-pass TM 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-P04lation Activates TK activity And provides docking sites For signal intermediates

Docking of Intracellular Signal molecules On 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 superfamily Also Ran, Rab, Rho. Bound to membrane by farnesyl lipid anchor

Downstream of Ras Raf Fos /Jun Erk

Modular organization of signal pathways by protein scaffolds Or 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 NF  B Pathway E.g. Gene activation by TNF-  Activate steps in immune & inflammatory responses in mammals, And Dorsal ventral axis determination in insects.