BIOB11H3 Lecture Notes - Lecture 24: Protein Kinase, Grb2, Platelet-Derived Growth Factor
Lec 24- Signal Transduction IV
Lecture Notes
• MAP Kinase Cascade
• RTKs play important roles in governing cell division
• Signal + receptor → Ras (activates) → Raf → MAP kinase cascade -→ Cell proliferation
• RAS: monomeric G-protein; activates Raf
• Raf: protein kinase
o Both are proto-oncogenes & get mutated into cancer causing oncogenes
• Fig 15-22: Steps of MAP kinase cascade
• 1. Binding of growth factor to its receptor
• 2. Autophosphorylation of tyrosine residues of the receptor
• 3. Recruitment of the Grb2-Sos proteins (Grb2 is an adaptor protein)
• 4. This complex causes the GTP-GDP exchange of Ras
• 5. Ras recruits the protein Raf (MAPKKK) to the membrane where it’s phosphorylated &
activated
• 6. Raf phosphorylated & activates another kinase named MEK (MAPKK)
• 7. MEK phosphorylated & activates ERK (MAPK)
o Steps 5-7 is characteristic of all MAP kinase cascades
• 8. MAPK translocates into the nucleus where it phosphorylates transcription factors
• 9. This leads to TFs affinity for regulatory sites on the DNA thus inc in transcription of
specific genes involved in growth response
• 10. MKP (MAP kinase phosphatase) feedback signaling to terminate signal by
inactivating ERK MAPK by removing phosphate groups
• MAP kinase cascade is involved in a variety of responses other than cell proliferation
• There are many diff kinds of MAPKKKs, MAPKKs & MAPKs
o This gives combinatorial control- diff combinations promote diff responses to a
variety of signaling molecules
• Pathway Interactions
• 1) Convergence: two diff stimuli activate pathways that share common downstream
effectors
o E.g. Both G-protein & RTK pathways converge by activation of diff PLC leading
to production of second messengers IP3 + DAG
o E.g. Fig 15-34: signals transmitted from a G-protein coupled receptor, an integrin
& a RTK all converge on Ras & then are transmitted along the MAP kinase
cascade
• 2) Divergence: a single stimulus can activate more than one type of signaling pathway
o E.g. Activation of RTK by either PDGF or EGF leads to transmission of signals
along 3 diff pathways
• 3) Cross-talk: one pathway affects the response of another pathway
o E.g. calcium ions released from SER by action of IP3 can act on various proteins
including PKC whose activity is also stimulated by DAG
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Document Summary
Binding of growth factor to its receptor: 2. Autophosphorylation of tyrosine residues of the receptor: 3. Recruitment of the grb2-sos proteins (grb2 is an adaptor protein: 4. This complex causes the gtp-gdp exchange of ras: 5. Ras recruits the protein raf (mapkkk) to the membrane where it"s phosphorylated & activated: 6. Raf phosphorylated & activates another kinase named mek (mapkk: 7. Mek phosphorylated & activates erk (mapk: steps 5-7 is characteristic of all map kinase cascades, 8. Mapk translocates into the nucleus where it phosphorylates transcription factors: 9. This leads to tfs affinity for regulatory sites on the dna thus inc in transcription of specific genes involved in growth response: 10. Both g-protein & rtk pathways converge by activation of diff plc leading to production of second messengers ip3 + dag: e. g. Fig 15-34: signals transmitted from a g-protein coupled receptor, an integrin.
