Transcript Growth Factors and Enzyme-Linked Receptor Signal Systems

Growth Factors and EnzymeLinked Receptor Signal Systems
Lecture 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 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
Erk
Fos
/Jun
Modular organization of signal pathways by protein scaffolds
Or lipid rafts
B-lymphocyte activation by antigen uses PI 3 Kinase & PLC-g
The Jak-STAT pathway, activated by a-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-kB Pathway
Activate steps in immune &
inflammatory responses
in mammals,
And Dorsal ventral axis
determination in insects.
E.g. Gene activation by TNF-a