Selective down-regulation of angiotensin II receptor type 1A signaling by protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells.
The heptahelical AT(1) G-protein-coupled receptor lacks inherent tyrosine kinase activity. Angiotensin II binding to AT(1) nevertheless activates several tyrosine kinases and stimulates both tyrosine phosphorylation and phosphatase activity of the SHP-2 tyrosine phosphatase in vascular smooth muscle cells. Since a balance between tyrosine kinase and tyrosine phosphatase activities is essential in angiotensin II signaling, we investigated the role of SHP-2 in modulating tyrosine kinase signaling pathways by stably transfecting vascular smooth muscle cells with expression vectors encoding wild-type SHP-2 protein or a catalytically inactive SHP-2 mutant. Our data indicate that SHP-2 is an efficient negative regulator of angiotensin II signaling. SHP-2 inhibited c-Src catalytic activity by dephosphorylating a positive regulatory tyrosine 418 within the Src kinase domain. Importantly, SHP-2 expression also abrogated angiotensin II-induced activation of ERK, whereas expression of catalytically inactive SHP-2 caused sustained ERK activation. Thus, SHP-2 likely regulates angiotensin II-induced MAP kinase signaling by inactivating c-Src. These SHP-2 effects were specific for a subset of angiotensin II signaling pathways, since SHP-2 overexpression failed to influence Jak2 tyrosine phosphorylation or Fyn catalytic activity. These data show SHP-2 represents a critical negative regulator of angiotensin II signaling, and further demonstrate a new function for this phosphatase in vascular smooth muscle cells.
Doan
Thanh
T
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Farmer
Paul
P
Cooney
Thomas
T
Ali
M Showkat
MS
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases
D016895:Culture Media, Serum-Free; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat