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.