Signal transduction biochemistry a field afflicted with many

“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, IP 3, ceramide). b. Cyclic nucleotides (c. AMP, c. GMP) 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/SH 2 interactions) Protein –phospholipid (PH/PIP 3 and many others) b. Protein-peptidyl motif (SH 3/RXXK or SH 3/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. 10 b The Biology of Cancer (© Garland Science 2007)

Figure 5. 32 a 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. 7 a 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. 7 a The Biology of Cancer (© Garland Science 2007)

Interaction of SH 2 domains and Phosphotyrosine/peptide sequence context s Figure 6. 8 a 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. 12 a The Biology of Cancer (© Garland Science 2007)

Figure 5. 12 b The Biology of Cancer (© Garland Science 2007)

Figure 5. 32 a 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 PI 3 Kinase Pathway Figure 6. 16 b The Biology of Cancer (© Garland Science 2007)

Figure 5. 7 b The Biology of Cancer (© Garland Science 2007)

Figure 16. 44 a 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. 24 a The Biology of Cancer (© Garland Science

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-k. B Pathway Figure 6. 29 a The Biology of Cancer (© Garland

Figure 7. 26 a 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. 29 b The Biology of Cancer (© Garland Science

In mammals there are four Notch receptors and 5 notch ligands (jagged 1, jagged 2, deltalike 1, 3 & 4) Osborne and Minter Nature Reviews Immunology 7, 64– 75 (January 2007)