NE102 Lecture Notes 3

Gaps inactivate ras by hydrolyzing gtp to gdp

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GAPs inactivate Ras by hydrolyzing GTP to GDP QUESTION: How is Ras activated by RTKs? The Ras GEF = a downstream signaling molecules activated by RTKs
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Dissecting MAP Kinase Signaling 18:04 Active Ras initiates a protein kinase cascade.  Begins with activation of the protein kinase Raf via protein-protein interactions ERK phosphorylates a variety of proteins to modulate cell behavior  QUESTION: How might you monitor whether MAP kinase signaling is active in cells?  MAP kinase signaling can be monitored by phosphor-ERK immunoblot Early 1990’s -> experiments defined the MAP Kinase pathway NEXT QUESTION: How does MAP Kinase signaling influence cell behavior? p42 and p44 are necessary for cell proliferation Add growth factors to fibroblast cell line = more cells Add dominant-negative ERK to fibroblast cell line Dominant-Negative proteins Mutated versions of a protein that blocks the activity of its normal/non-mutated  counterpart Create expression plasmid to transfect into cells Signaling pathway will be blocked and ERK’s activity will be inhibited Several subsequent studies further demonstrated that MAP kinase signaling induces  cell proliferation Progress in research yielded drugs that inhibit specific proteins in the MAP kinase  pathways Ex.) U0126 = MEK inhibitor QUESTION: How might you confirm that U0126 is actually blocking ERK activation?  Phospho-ERK blot
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Dissecting MAP Kinase Signaling 18:04 NEXT QUESTION: How does ERK induce cell proliferation? One key target = the transcription factor complex Elk-1/SRF Phosphoryltion by ERK activates the Elk-1/SRF complex -> transcription of Elk-1/SRF  target genes What genes Elk-1/SRF might activate to induce cell proliferation? Cyclins! Cyclin/Cdk complexes drive progression through the cell cycle OVERALL CONCLUSION: MAP Kinase signaling functions to regulate cell proliferation  in response to growth factors PC12 Cells: Pheochromocyoma cell line derived from a rat adrenal tumor Treatment with NGF induces differentiation into neuron-like cells
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Integrating Concepts through PC12 Differentiation 18:04 NUMEROUS STUDIES AND CORROBORATIN EVIDENCE: MAP kinase signaling promotes cell proliferation in response to growth factors. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells  which respond to nerve growth actor Pehochromocytoma = tumor cells within adrenal gland KEY OBSERVATION: NGF induces neuronal differentiation of PC12 cells!
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