Transcript “Signal transduction biochemistry: a field afflicted with many facts and blessed with only a few unifying principles.” R.

“Signal transduction biochemistry: a field
afflicted with many facts and blessed with
only a few unifying principles.”
R. A. Weinberg
Figure 6.2 The Biology of Cancer (© Garland Science 2007)
Some Common Themes & Challenges of Signal Transduction
Intracellular communication evolved to meet the challenges of: Specificity, Access & Deactivation
Common Themes
1. Signal transduction pathways are turned ON by the arrival of a signal.
2. The involvement of a receptor
a. Typically, ectodomains of transmembrane receptors bind impermeable ligands.
b. Lipophilic signals that traverse the membrane are bound by intracellular receptors.
3. Modifications to existing molecules that involve making or breaking covalent bonds
a. The action of kinases and phosphatases.
b. Proteolytic cleavage.
c. Covalent additions
4. The Generation of second messengers.
There are many different second messengers and the list includes:
a. Agents derived from membrane phospholipids (DAG, IP3, ceramide).
b. Cyclic nucleotides (cAMP, cGMP)
c. Ca+2
d. Gases (No in bacteria and eucaryotes; ethylene in plants)
5. Small and large G proteins
6.The induced assembly or targeted translocation of critical components of the signal transduction pathway.
Many signal transduction pathways depend upon the induced assembly of critical components
a. Protein-modified peptide (these include Phosphotyrosine/SH2 interactions)
Protein –phospholipid (PH/PIP3 and many others)
b. Protein-peptidyl motif (SH3/RXXK or SH3/PXXXP and many others)
c. Protein domain-protein domain
d. Adaptor proteins link different protein components into signaling complexes.
7. Cascades to amplify and relay signals
8. Compartmentation.
9. Signal transdution pathways interact with each other (‘crosstalk’ is the rule rather than the exception).
10. The default setting for signal transduction pathways is OFF
Association Motifs and Modules
Some key signaling molecules
bearing Src homology modules
Figure 6.10b The Biology of Cancer (© Garland Science 2007)
Figure 5.32a The Biology of Cancer (© Garland Science 2007)
Figure 5.1 The Biology of Cancer (© Garland Science 2007)
Lessons From Src
The Product of the SRC gene Phosphorylates Tyrosine
Figure 5.8 The Biology of Cancer (© Garland Science 2007)
Use of Antibody and Absorption to Analyze
Patterns of Protein Expression
Lane:
1-3 Uninfected cell lysate
4-6
Cells infected with Src- RSV
7-9 Cells infected with wild type RSV
Lane 7: normal rabbit serum
Lane 8: tumor-bearing rabbit serum
Lane 9: Preincub. with RSV lysate
Figure 5.6 The Biology of Cancer (© Garland Science 2007)
Effects of a Src Kinase on Phosphoprotein Profile
Figure 5.7a The Biology of Cancer (© Garland Science 2007)
Anatomy Of The EGF Receptor & Some Other Receptors
The EGF receptor and the
other receptors displayed
above contain sequences
that are related to the
tyrosine kinase domain of
Src.
3-D Structure of Src
Figure 6.7a The Biology of Cancer (© Garland Science 2007)
Interaction of SH2 domains and Phosphotyrosine/peptide sequence
context
s
Figure 6.8a The Biology of Cancer (© Garland Science 2007)
Some Growth Factor Receptors Can Engage Many Key Signaling Molecules
Figure 6.9 The Biology of Cancer (© Garland Science 2007)
Figure 5.15 The Biology of Cancer (© Garland Science 2007)
Figure 5.12a The Biology of Cancer (© Garland Science 2007)
Figure 5.12b The Biology of Cancer (© Garland Science 2007)
Figure 5.32a The Biology of Cancer (© Garland Science 2007)
Figure 6.12 The Biology of Cancer (© Garland Science 2007)
The Ras Initiates A Key Pathway That Recruits
Many Other Powerful Pathways
Figure 6.15 The Biology of Cancer (© Garland Science 2007)
Figure 5.30 The Biology of Cancer (© Garland Science 2007)
Two 3-D Views of Ras
The Ras – GTP Complex
Figure 5.31 The Biology of Cancer (© Garland Science 2007)
Key residues for Ras interaction
with substrate and other pathways
The PI3 Kinase Pathway
Figure 6.16b The Biology of Cancer (© Garland Science 2007)
Figure 5.7b The Biology of Cancer (© Garland Science 2007)
Figure 16.44a The Biology of Cancer (© Garland Science 2007)
Figure 6.21 The Biology of Cancer (© Garland Science 2007)
Large G-Protein Coupled Pathways
Figure 6.28 The Biology of Cancer (© Garland Science 2007)
Integrin Receptor Pathways
Figure 6.24a The Biology of Cancer (© Garland Science 2007)
b-Catenin – An Adhesion Molecule & Signal Transducer
Inactive
Figure 5.24 The Biology of Cancer (© Garland Science 2007)
The JAK/STAT Pathway
Figure 6.22 The Biology of Cancer (© Garland Science 2007)
The TGF-b Pathway
Figure 5.21 The Biology of Cancer (© Garland Science 2007)
The Hedgehog Pathway
Figure 5.23 The Biology of Cancer (© Garland Science 2007)
The NF-kB Pathway
Figure 6.29a The Biology of Cancer (© Garland Science 2007)
Figure 7.26a The Biology of Cancer (© Garland Science 2007)
Signalling Pathways of Innate and Adaptive Receptors
Rawlings et al. Nature Reviews Immunology 6, 799–812 (November 2006)
The Notch Pathway
Figure 6.29b The Biology of Cancer (© Garland Science 2007)
In mammals there are four Notch receptors
and 5 notch ligands (jagged1, jagged2, deltalike 1, 3 & 4)
Osborne and Minter Nature Reviews Immunology 7, 64–75 (January 2007)
Figure 6.33 The Biology of Cancer (© Garland Science 2007)
Figure 6.32 The Biology of Cancer (© Garland Science 2007)