PLCβ1-SHP-2 complex, PLCβ1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

Journal of Biomedical Science

Giulio Clari¹  Achille C Pessina³  Gian Paolo Rossi³  Lucia Dal Maso³  Elisa Pagnin³  Paul A Davis²  Luciana Bordin¹  Lorenzo A Calò³ 

[1]Department of Biological Chemistry, University of Padova, School of Medicine, Italy

[2]Department of Nutrition, University of California, Davis, USA

[3]Department of Clinical and Experimental Medicine, Clinica Medica 4 University of Padova, School of Medicine, Italy

关键词: SHP-2-PLCβ1 complex;    PLCβ1;    SHP-2;    Angiotensin II signaling;   

Others  :  833451
DOI  :  10.1186/1423-0127-18-38

 received in 2011-03-22, accepted in 2011-06-13,  发布年份 2011

【 摘 要 】

Background

Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified.

Results

Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCβ1 are present as a preformed complex. Complex PLCβ1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLCβ1 complexes and caused complex associated PLCβ1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCβ1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2.

Conclusions

Ang II signals are shown for the first time to involve a preformed SHP-2-PLCβ1 complex. Changes in the complex's PLCβ1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLCβ1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCβ1 tyr-phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system.

【 授权许可】

   
2011 Calò et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Mehta PK, Griendling KK: Angiotensin II Cell Signaling. Physiological and Pathological Effects in the Cardiovascular System. Am J Physiol Cell Physiol 2007, 92:C82-C97.
• [2]Berridge MJ: Inositol trisphosphate and calcium signalling. Nature 1993, 361:315-25.
• [3]Davis MJ, Hill MH: Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 1999, 70:387-423.
• [4]Touyz RM: Role of angiotensin II in regulating vascular structural and functional changes in hypertension. Curr Hypertens Rep 2003, 5:155-64.
• [5]Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW: Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. J Biol Chem 1998, 273:19772-7.
• [6]Tabet F, Schiffrin EL, Callera GE, He Y, Yao G, Ostman A, Kappert K, Tonks NK, Touyz RM: Redox-Sensitive Signaling by Angiotensin II Involves Oxidative Inactivation and Blunted Phosphorylation of Protein Tyrosine Phosphatase SHP-2 in Vascular Smooth Muscle Cells From SHR. Circ Res 2008, 103:149-58.
• [7]Ali MS, Schieffer B, Delafontaine P, Bernstein KE, Ling BN, Marrero MB: Angiotensin II Stimulates Tyrosine Phosphorylation and Activation of Insulin Receptor Substrate 1 and Protein-tyrosine Phosphatase1D in Vascular Smooth Muscle Cells. J Biol Chem 1997, 272:12373-9.
• [8]Maegawa H, Hasegawa M, Sugai S, Obata T, Ugi S, Morino K, Egawa K, Fujita T, Sakamoto T, Nishio Y, Kojima H, Haneda M, Yasuda H, Kikkawa R, Kashiwagi A: Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. J Biol Chem 1999, 274:30236-43.
• [9]Doan T, Farmer P, Cooney T, Ali MS: Selective down-regulation of angiotensin II receptor type 1A signaling by protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells. Cell Signal 2004, 16:301-11.
• [10]Klaman LD, Chen B, Araki T, Harada H, Thomas SM, George EL, Neel BG: An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev Cell 2006, 10:317-27.
• [11]Bregeon J, Loirand G, Pacaud P, Rolli-Derkinderen M: Angiotensin II induces RhoA activation through SHP2-dependent dephosphorylation of the RhoGAP p190A in vascular smooth muscle cells. Am J Physiol Cell Physiol 2009, 297:C1062-70.
• [12]Loirand G, Guerin P, Pacaud P: Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006, 98:322-34.
• [13]Calò LA, Pessina AC: RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. J Hypertens 2007, 25:259-64.
• [14]Golebiewska U, Scarlata S: Galphaq binds two effectors separately in cells: evidence for predetermined signaling pathways. Biophys J 2008, 95:2575-82.
• [15]Calò LA: Vascular tone control in humans: the utility of studies in Bartter's/Gitelman's syndromes. Kidney Int 2006, 69:963-6.
• [16]Calò LA, Pessina AC, Semplicini A: Angiotensin II signaling in the Bartter's and Gitelman's syndromes, a negative human model of hypertension. High Blood Press Cardiovasc Prev 2005, 12:17-26.
• [17]Calò LA, Puato M, Schiavo S, Zanardo M, Tirrito C, Pagnin E, Balbi G, Davis PA, Palatini P, Pauletto P: Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways. Nephrol Dial Transplant 2008, 23:2804-9.
• [18]Calò LA, Montisci R, Scognamiglio R, Davis PA, Pagnin E, Schiavo S, Mormino P, Semplicini A, Palatini P, D'Angelo A, Pessina AC: High angiotensin II state without cardiac remodeling (Bartter's and Gitelman's syndromes): are angiotensin II type 2 receptors involved? J Endocrinol Invest 2009, 32:832-6.
• [19]Calò LA, Schiavo S, Davis PA, Pagnin E, Mormino P, D'Angelo A, Pessina AC: Angiotensin II signaling via type 2 receptors in a human model of vascular hyporeactivity: implications for hypertension. J Hypertens 2010, 28:111-8.
• [20]Wieland T, Lutz S, Chidiac P: Regulators of G protein signaling: a spotlight on emerging functions in the cardiovascular system. Curr Opin Pharmacol 2007, 7:1-7.
• [21]Gu S, Cifelli C, Wang S, Heximer SP: RGS proteins: identifying new GAPs in the understanding of blood pressure regulation and cardiovascular function. Clin Sci 2009, 116:391-9.
• [22]Zheng H, Alter S, Qu CK: SHP-2 tyrosine phosphatase in human diseases. Int J Clin Exp Med 2009, 2:17-25.
• [23]Neel BG, Gu H, Pao L: The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 2003, 28:284-93.
• [24]Qu CK: Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochim Biophys Acta 2002, 1592:297-301.
• [25]Wang Q, Downey GP, Herrera-Abreu MT, Kapus A, McCulloch CA: SHP-2 modulates interleukin-1-induced Ca2+ flux and ERK activation via phosphorylation of phospholipase Cgamma1. J Biol Chem 2005, 280:8397-406.
• [26]Filtz TM, Grubb DR, McLeod-Dryden TJ, Luo J, Woodcock EA: Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase Cbeta1b. FASEB J 2009, 23:3564-70.
• [27]Calò LA, Pagnin E, Ceolotto G, Davis PA, Schiavo S, Papparella I, Semplicini A, Pessina AC: Silencing regulator of G protein signaling-2 (RGS-2) increases angiotensin II signaling: insights into hypertension from findings in Bartter's/Gitelman's syndromes. J Hypertens 2008, 26:938-45.
• [28]Semplicini A, Lenzini L, Sartori M, Papparella I, Calò LA, Pagnin E, Strapazzon G, Benna C, Costa R, Avogaro A, Ceolotto G, Pessina AC: Reduced expression of regulator of G protein signaling-2 in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II. J Hypertens 2006, 24:1115-24.
• [29]Calo L, Ceolotto G, Milani M, Pagnin E, van den Heuvel LP, Sartori M, Davis PA, Costa R, Semplicini A: Abnormalities of Gq-mediated cell signaling in Bartter and Gitelman syndromes. Kidney Int 2001, 60:882-9.
• [30]Pagnin E, Davis PA, Sartori M, Semplicini A, Pessina AC, Calo LA: Rho kinase and PAI-1 in Bartter's/Gitelman's syndromes: relationship to angiotensin II signaling. J Hypertens 2004, 22:1963-9.