Cell Signaling Lecture 10.

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Cell Signaling Lecture 10

Ras/MAP Kinase Pathway Receptor tyrosine kinase Cytokine receptors G Protein Activate this pathway Ras Activation of Ligand Binding to Receptor Formation of Regulation of Transcription factor MAP Kinase Activation of Kinase cascade

Ras A small (~170 AA) monomeric G protein belongs to the GTPase superfamily of switch proteins. Like Gα subunits in trimeric G proteins, Ras alternates between an active ‘on’ state (when bound to GTP) and an inactive ‘off ‘ state (when bound to GDP). Unlike trimeric G proteins, Ras is not directly linked to cell-surface receptor

Guanine Nucleotide Exchange Factor (GEF) Activation of Ras Ras Ras Binds to Ras.GDP complex and releases GDP GDP GTP Guanine Nucleotide Exchange Factor (GEF) GTP present in abandance in cytosol attaches Ras Ras Ras GTPase-activating protein (GAP) binds to Ras-GTP complex upon completion of a reaction and hydrolyze GTP to GDp

Mutation in Ras Mutant Ras proteins are associated with many types of human cancer. Mutant Ras can bind GTP but can not hydrolyze it and are permanently in the ‘on’ state and contribute to oncogenic transformation. Active Ras protein (RasD) contain a mutation at position 12. Replacement of the normal glycine-12 with any other AA except proline blocks the functional binding of GAP and in essence locks Ras in the active GTP-bound state.

RTK are linked to Ras by adopter proteins Activated ligand bound RTK cannot directly activate Ras. 2 cytosolic proteins GRB2 and Sos must be first recruited to provide a link between the receptor and Ras. An SH2 domain in GRB2 binds to a specific phosphotyrosine residue in the activated receptor. GRB2 also contain 2 SH3 domains which binds to and activate Sos. Thus fuctions as an adopter for many RTK. Sos is a guanine-nucleotide exchange factor (GEF) which dissociates GDP from Ras.

RTK are linked to Ras by adopter proteins SH3 SH2 GRB2 Sos (GEF) SH2 GRB2 SH3 Sos (GEF) The SH3 domain of GRB2 binds to Sos on proline rich sequences. Binding of Sos to inactive Ras causes a confirmational change