Lectures_6_and_7-phosphorylation

(dag/ip3 pathway pi3kinase(activation of akt

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Unformatted text preview: (DAG/IP3 pathway), PI3Kinase (activation of Akt pathway=cell survival); Grb2 is an adaptor and activates MAPK pathways through small G proteins • Inactivated by rapid internalization of receptor + ligands Non-Receptor Tyrosine Kinases • Include Src , Jak, Abl, Tec and Fak (with Src tyrosine kinase family being the best described) • NRTKs have catalytic domain which is a functional enzyme • Regulatory domains maintain low Tyr P activity, target the protein to specific subcellular compartments, interact with protein substrates and bind to other signaling molecules (linkers) • Domains of Src kinases include SH4 (Src Homology 4), SH3, SH2 and SH1 – SH1 is the catalytic domain and C-terminal to it is a regulatory domain that controls activity; inhibited by Y527 P’lation and activated by de-P; if you’re missing Y527, you don’t have the “off-switch” tumors – SH2 and SH3 are the molecular adhesive domains (protein-protein interactions); SH3 recognizes proline-rich sequences and binds to them and the affinity can be regulated by Tyr P’lation; SH2 recognizes specific p-Tyr residues – SH4 plays a role in membrane attachment and interacts with heads of phospholipids in membrane; PKA P’lation of Ser217 of Src causes it to dissociate from membrane NRTK Regulation 1) Occurs via Ser/Thr protein kinases (or Ca2+) acting directly on the NRTK (e.g., PKA) 2) Occurs via activation of receptors that contain an SH2 domain NRTKs can link up to these and “borrow” the receptor activation 3) Occurs via autophosphorylation which can occur if 2 NRTKs come into contact (similar to RTKs) Dephosphorylation by Phosphatases • Also classified as protein Ser/Thr or protein Tyr phosphatases with multiple subtypes Ser/Thr phosphatases PP1: most prevalent in mammals; wide variety of substrates; can be localized to specific subcellular compartments (e.g., PSD); certain inhibitor proteins can influence function ( DARPP-32 ) PP2A: cytoplasmic and in nucleus PP2B: calcineurin ; Ca2+/calmodulin-dependent; enriched in striatum; broad substrate specificity; binds to AKAPs; activity is regulated by immunophilins (immunosuppressive drugs promote action of calcineurin) calcineurin Dephosphorylation by Phosphatases • PTPs (protein tyrosine phosphates) account principally for the low level of P-Tyr in our cells • Out-number PTKs by 10-1,000 times NRTPs: catalytic domains are unrelated to that of Ser/Thr phosphatases; have sites that “attack” the P-Tyr on the substrate; has a subdomain that confers specificity of the substrate; some have SH2 domains ( SHPs )-SHP1 deP the auto-P RTK inactivation-SHP2 recruits Grb2 to the RTK activates the MAPK pathway RTPs: also have extracellular, transmembrane and cytosolic domains like RTKs-some have constitutive activity while others can be ligand-gated (e.g., CD45) and might dimerize...
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(DAG/IP3 pathway PI3Kinase(activation of Akt pathway=cell...

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