GIT1 Mediates Src-dependent Activation of Phospholipase Cγ by Angiotensin II and Epidermal Growth Factor

Critical events for vasoconstrictor and growth factor signal transduction include stimulation of phospholipase Cγ (PLCγ) and elevation of intracellular calcium. c-Src has been proposed as a common mediator for these signals activated by both G protein-coupled receptors (GPCRs) and tyrosine kinase-co...

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Veröffentlicht in:The Journal of biological chemistry 2003-12, Vol.278 (50), p.49936-49944
Hauptverfasser: Haendeler, Judith, Yin, Guoyong, Hojo, Yukihiro, Saito, Yuji, Melaragno, Matthew, Yan, Chen, Sharma, Virendra K., Heller, Manfred, Aebersold, Ruedi, Berk, Bradford C.
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Sprache:eng
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Zusammenfassung:Critical events for vasoconstrictor and growth factor signal transduction include stimulation of phospholipase Cγ (PLCγ) and elevation of intracellular calcium. c-Src has been proposed as a common mediator for these signals activated by both G protein-coupled receptors (GPCRs) and tyrosine kinase-coupled receptors (TKRs). Here we show that the GPCR kinase-interacting protein-1 (GIT1) is a substrate for c-Src that undergoes tyrosine phosphorylation in response to angiotensin II (AngII) and EGF in vascular smooth muscle and 293 cells. GIT1 associates with PLCγ via the PLCγ Src homology 2 and 3 domains constitutively, and the interaction is unaltered by AngII and EGF. GIT1 interaction with PLCγ is required for PLCγ activation based on inhibition of tyrosine phosphorylation and calcium mobilization after GIT1 knockdown with antisense GIT1 oligonucleotides. GIT1 interacts with PLCγ via a novel Spa homology domain (SHD) and a coiled-coil domain. Deletion mutation analysis showed that GIT1(SHD) is required for AngII- and EGF-mediated PLCγ activation (measured by phosphorylation of Tyr783 and inositol 1,4,5-trisphosphate formation). We propose that GIT1 is a novel regulator of PLCγ function that mediates PLCγ activation by c-Src and integrates signal transduction by GPCRs and TKRs.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M307317200