BIOL 212 Lecture Notes - Lecture 26: Mitogen-Activated Protein Kinase Kinase, Protein Kinase, Lipid-Anchored Protein
18 May 2018
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Lecture 26 Notes
Enzyme Coupled Receptors: Receptor Tyrosine Kinases (RTKs)
- Activation of RTK stimulates assembly or intracellular signaling complex
- Activated intracellular kinase region in one receptor molecule phosphorylates tyrosine residues on
second molecules of receptor, occurs in both directions
- Signal molecule in form of a dimer → kinase activity stimulated by dimerization →active RTKs →
activation of downstream intracellular signaling pathways
TRK-activated Intracellular Signaling Complex Relays Signal to Ras
- Ras is a GTP-binding molecular switch
- Ras GDP → GEF turns Ras ON → RAS GTP → GAP turns Ras off
- Ras activated by RTK via recruitment adaptors and GEFs
- Ras has lipid anchor and localized on cytosolic side of plasma membrane
- Ras activates MAP kinase cascade
- Activated Ras protein → activated MAP kinase kinase kinase (MAPKKK) → activated MAP kinase
kinase (MAPKK) → activated MAP kinase (MAPK) → changes protein activity or changes gene
expression
Cellular Responses to MAPK Signaling
- Substrates in:
o Nucleus, cytosol, membranes, cytoskeleton (more than 250)
- Cellular processes:
o Cell proliferation, cell survival, differentiation, apoptosis, motility, metabolism
- Activated forms of Ras are responsible for 30% human cancers
Ras
- Constitutively active form Ras cannot hydrolyze GTP and signals all the time, even w/o receptor
activation, thus continuous transmission of signal along multiple pathways in absence of EC signal
molecule
- Constitutively active form Ras help order signaling pathways
- X acts before Ras (active Ras does not need X)
- Y acts after Ras (active Ras needs Y)
RTK Signals Relayed via PI 3-kinase/Akt Signaling Pathway
- Pi 3-kinase = phosphoinositide 3-kinase, Akt is also known as protein kinase B or PKB
- Survival signal → activated RTK → activated Pi 3-kinase → phosphorylated inositol phospholipid →
protein kinase 1 and protein kinase 2 → Akt activated → signal relayed onward by activated Akt
- Pi 3-kinase phosphorylates Pi 4,5-biphosphate which is also a substrate for Phospholipase C
Akt
- Promotes cell growth and cell survival
- Akt activates cell survival pathways (inhibits apoptosis)
o Bcl2 inhibits apoptosis. Bad inhibits Bcl2, so Bad indirectly promotes apoptosis. Akt inactivates
Bad, so Akt indirectly inhibits apoptosis (promotes cell survival)
Signal Integration
- Signaling pathways can integrate information to control complex cell behaviors
- Ex. 2 phosphorylation events are required for transmission of signal
- Cell signaling pathways can converge on common target genes
- New patterns of gene expression and cell differentiation
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Document Summary
Activation of rtk stimulates assembly or intracellular signaling complex. Activated intracellular kinase region in one receptor molecule phosphorylates tyrosine residues on second molecules of receptor, occurs in both directions. Signal molecule in form of a dimer kinase activity stimulated by dimerization active rtks activation of downstream intracellular signaling pathways. Trk-activated intracellular signaling complex relays signal to ras. Ras gdp gef turns ras on ras gtp gap turns ras off. Ras activated by rtk via recruitment adaptors and gefs. Ras has lipid anchor and localized on cytosolic side of plasma membrane. Activated ras protein activated map kinase kinase kinase (mapkkk) activated map kinase kinase (mapkk) activated map kinase (mapk) changes protein activity or changes gene expression. Substrates in: nucleus, cytosol, membranes, cytoskeleton (more than 250) Cellular processes: cell proliferation, cell survival, differentiation, apoptosis, motility, metabolism. Activated forms of ras are responsible for 30% human cancers.
