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CellSignaling08Lec4 - Adaptor proteins can be composes...

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Adaptor proteins can be composes almost entirely of SH2 and SH3 domains – work to Couple tyrosine- phosphorylated proteins to other proteins that do not have their own SH2 domains. *** Important – because such adaptor proteins help couple activated receptors to RAS
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RAS is a key component of many receptor tyrosine kinase cascades. RAS first discovered as a viral oncogene. *subsequent studies indicate that an altered (hyperactive) RAS gene is found in about 30% of all human tumors. RAS proteins belong to the large superfamily of monomeric GTPases .
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The RAS Superfamily Ras H,K,N  Ras Relay signals from  RTKs Rho Rho,Rac, Cdc42 Relay signals ARF ARF1 -  ARF6 Vesicle protein coat  assembly Rab Rab1 -  60 Vesicular trafficking Ran Ran Mt assembly and  nuclear transport
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EXAMPLE: Early Cell-signaling Events in Drosophila Eye Development. Sevenless
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Ras Activates : A Serine/Threonine phosphorylation Cascade – MAP-Kinase. MAP = M itogen- A ctivated P rotein Many s/t kinases participate in the cascade. Core module consists of 3 Kinases. Terminal kinase is MAP-Kinase **Unusual feature of MAP Kinase - requires two phosphorylation events for full activation.
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Ras Activates : A Serine/Threonine phosphorylation Cascade – MAP-Kinase.
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Inactive Raf Active Raf 14-3-3 C-terminal Kinase domain N-terminal Regulatory domain
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ATP ADP Raf activates MEK MEK activates MAPK ATP ADP
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There are multiple three component MAP kinase signaling modules. Different ones mediate different responses in the same cell. Can be activated by different receptors, i.e. G-protein linked receptors in yeast. Some of the MAP Kinase modules use one or more of the same kinases – yet activate different effector proteins.
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Key Concept: Scaffold Proteins Help Organize and Prevent Crosstalk between parallel MAP Kinase Modules
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Key Concept: The building of Intracellular Signaling Complexes onto scaffold proteins, enhances speed, efficiency and specificity of the response.
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P P P P P Tyr - 1009 Tyr - 771 Tyr - 751 Tyr- 740 Tyr - 1021 Phospholipase C- γ GTPase- activating protein (GAP) PI 3-kinase (regulatory subunit) SH2 domains SH3 domain PDGF receptor
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PI3-kinase – (phosphatidylinositol 3- kinase) is involved in one of the major intracellular signaling pathways that leads to cell growth. It principally phosphorylates inositol phospholipids. Can be activated by Receptor tyrosine kinases, as well as others*.
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