Lectures_6_and_7-phosphorylation

• originally identified as being stimulated by

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Unformatted text preview: • Originally identified as being stimulated by mitogens in cell growth and were shown in brain to be microtubule-associated (either way, it’s MAPK) Mitogen-activated Protein Kinases (MAPKs) • Activation of signaling begins with the stimulation of small G proteins ( Ras and Rac ) • Involves a number of linker proteins that couple the small G potein (e.g. Ras) to the RTK • Small G protein activation leads to a series of kinase P’lations (chain of P) Small G Proteins • Large superfamily of G proteins that are smaller in molecular weight than the heterotrimeric G proteins • L i k e , they bind guanine nucleotides, have GTPase activity and undergo a change in affinity for targets when GTP binds • Molecular switches that control a variety of specific cell functions Small G Proteins • Activity is regulated by: • GEFs (guanine nucleotide exchange factors) increase activity) • GAPs (GTPase-activating proteins) inhibit activity (like RGS) • GIPs (GTPase-inhibiting proteins) increase activity and then inhibit (AGS3-like) BARK/GRK GRK : G protein receptor kinase G protein receptor desensitization Low stimulation: 1-Gs AC cAMP PKA 2-PKA P-coupling site for s 3-uncoupling =negative feedback High stimulation: 1-GRK is activated 2-P of distal sites on receptor 3-recruitment of arrestin 4-uncouples s =negative feedback BARK=Beta adrenergic receptor kinase (first one to be discovered) Tyrosine P’lation • Occurs via protein tyrosine kinases (PTKs) • This general family includes ligand-activated tyrosine kinase receptors (RTKs ; e.g., the receptors for growth factors, neurotrophins etc) or non- receptor protein tyrosine kinases (NRTKs ) • RTKs are localized to PM while NRTKs are distributed in different cellular compartments • As with Ser/Thr P’lation, Tyr P’lation is controlled by PTKs and protein tyrosine phosphatases (PTPs) • PTKs catalyze the transfer of P from ATP to Tyr on protein substrates Receptor Tyrosine Kinase Superfamily • Consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain • Extracellular domain: incredibly varied from family to family but all contain the ligand binding domain • (soluble molecules like neurotrophins, adhesion molecules expressed on other cells) • Transmembrane domain : hydrophobic, low degree of homology across different families; job is to anchor receptor in membrane • Cytoplasmic domain: catalytic domain (SH1) and various autophosphorylation sites, docking sites of SH2-containing proteins (e.g., NRTKs) RTK Activation • Ligand binding receptor dimerization transphosphorylation or autophosphorylation on Tyr catalytic activity • Ligand binding recruitment of SH2-containing signaling molecules including various NRTKs, PLC- (DAG/IP3 pathway), PI3Kinase (activation...
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• Originally identified as being stimulated by mitogens...

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