1. Brief Review – Growth Factors and Receptors
most growth factors are secreted
receptors are transmembrane proteins
3 major features:
extracellular domain
transmembrane region
intracellular domain
where, when, and
how they are expressed
determines their biological
function

2. FIGURE 26-3: Schematic structures of receptor protein tyrosine kinase (RPTK) families. RPTKs can be divided into different families according to the structural features in the extracellular domain. Following the extracellular domain are the transmembrane and intracellular domains; the latter contains the catalytic domain. (Adapted from Blume-Jensen & Hunter, 2001 with permission.)
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

3. FIGURE 26-4: Nonreceptor protein tyrosine kinase (NRPTK) families
FIGURE 26-4: Nonreceptor protein tyrosine kinase (NRPTK) families. The family members are shown to the right and family name to the left of each NRPTK. Inset indicates the PTK catalytic domain and other domains for the regulation of localization and function. Kinases listed in bold have been associated with malignancies in humans and/or animal models. (Adapted from Blume-Jensen & Hunter, 2001 with permission.)
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

4. FIGURE 26-5: SH2, SH3 and phosphotyrosine binding (PTB) domain-containing signaling proteins. SH2, SH3 and PTB domains are important molecular ‘adhesives’. These domains are found in enzymes and play important roles in the regulation of enzyme function. They also are found in proteins lacking any apparent catalytic domain, in which case they may serve as adaptor proteins, assembling signal-transduction complexes. The PTB domain of insulin receptor substrate-1 (IRS-1) shares a low degree of homology with the one on SHC. The black circle indicates a myristic acid moiety. PLC, phospholipase C; PI3-kinase, phosphatidylinositol-3-kinase; PTP, protein tyrosine phosphatase; PH, pleckstrin homology; SHP, SH2-containing PTP; Grb, growth-factor-receptor-binding protein.
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

5. Brief Review – Receptor Activity
intracellular, or catalytic, domain has kinase activity
kinases add phosphate groups to (phosphorylate)
specific amino acids
ATP-binding
Phospho-transferase
ATP P
Amino Acid P
ADP

6. Consequences of RTK activation
GROWTH
FACTOR
PIP3
PIP3
RTK
SOS
Grb2
RAS
RAS P P P
PI3K
p85
p110
Akt
PDK1
Raf P
MEK P P
GSK3 P P P P
BAD
NF-ĸB
MDM2
p70S6K
FKHR P
ERK
PROLIFERATION
CELL SURVIVAL
PROTEIN SYNTHESIS
. Aaronson, Growth factor and receptor tyrosine kinases. Sci. STKE 2005, tr6 (2005).

7. Intracellular Signaling
begins with autophosphorylated or transphosphorylated
amino acids on the receptor
Phosphorylation recruits other proteins to the receptor
Amino acids surrounding the phosphorylation site
determine which proteins are bound…
4 major protein interaction domains:
SH2, PTB, SH3, PH
Membrane
-Tyr P
Kinase Domain
-Tyr P

8. TABLE 26-1: Specificity and Affinity of SH2, Phosphotyrosine Binding (PTB) and SH3 Domains
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

9. Basics of Amino Acid Structure

10. Basics of Protein Structure
Primary Structure =
“beads on a string”
Quaternary Structure =
specific folding creates
domains, or “units” of the
protein

11. SH2 domains SH2 = src homology 2
was first identified as a 100 amino acid region of
homology (“sameness”) in the src tyrosine kinase
specifically recognizes phosphorylated Tyrosine
2 classes of SH2 domain-containing proteins…
- have enzymatic activity (like Src)
- don’t have enzymatic activity
Those with no enzymatic activity bind other
proteins to the receptor…adaptor molecules

12. SH2 domain specificity
specificity is determined by the amino acids C-terminal
to the phospho-Tyr
in most cases, it is the amino acid at position +3 that
determines specificity
Hydrophobic amino acid
Science, Vol 278, Issue 5346, , 19 December 1997

13. PTB domains phosphotyrosine binding domains recognize amino
acids N-terminal to the phospho-Tyr
PTB-containing proteins also participate in hormone
signaling
any amino acid
Science, Vol 278, Issue 5346, , 19 December 1997

14. SH3 domains src homology 3 domains recognize amino acid
sequences rich in Proline (Pro-rich)
Is a more general protein-protein interaction motif…
many cytoskeletal proteins contain it
any amino acid
Science, Vol 278, Issue 5346, , 19 December 1997

15. PH domains pleckstrin homology domains recognize phospholipids
(components of the plasma membrane)
Science, Vol 278, Issue 5346, , 19 December 1997

16. Protein-Protein Interactions and Receptors
Proteins with many different interaction domains
can bind to growth factor receptor family members
Protein-protein
interactions connect
receptors to their
intracellular signaling
networks
Figure 6.9 The Biology of Cancer (© Garland Science 2007)

17. Receptors bind other Kinases,
and Adaptor Proteins
Figure 6.10a The Biology of Cancer (© Garland Science 2007)

18. EGFR and the Ras Pathway
SOS
Grb2
RAS P P
Raf P
MEK
Grb2: adaptor protein that binds to
phosphorylated Tyr on EGFR using
its SH2 domain P
ERK
PROLIFERATION
CELL SURVIVAL
. Aaronson, Growth factor and receptor tyrosine kinases. Sci. STKE 2005, tr6 (2005).

19. PI3K Target(s) PI3K phosphorylates PIP2 to make PIP3
PIP3 is now a binding site for Akt…
Figure 6.19a The Biology of Cancer (© Garland Science 2007)