SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor

Ekman, Simon; Kallin, Anders; Engström, Ulla; Heldin, Carl‐Henrik; Rönnstrand, Lars

doi:10.1038/sj.onc.1205210

Cited by 41 publications

(34 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, studies that have been done so far on PDGF receptor dephosphorylation support the notion that selectivity in dephosphorylation is a common feature. Deletion of the binding site for SHP-2 results in a specific increase in the phosphorylation of Y771 in PDGF ␣ and ␤ receptor heterodimeric complexes (9). Also, DEP-1 dephosphorylation of the PDGF ␤ receptor displays site selectivity, with Y1021 and Y857 occurring as preferred and nonpreferred sites, respectively (22,32).…”

Section: Discussionmentioning

confidence: 99%

“…The peptides were conjugated to keyhole limpet hemocyanin by using m-maleimido benzoyl-N-hydroxysuccinimide ester (Pierce), and the conjugates were used to immunize rabbits. The antibodies were affinity purified by passing the antiserum over three consecutive columns of immobilized nonphosphorylated peptide, phosphotyrosine-agarose, and phosphorylated peptide as previously described (9). The peptides were coupled to Sulfolink (Pierce) and phosphotyrosine was coupled to Affigel 10 (Bio-Rad) according to the manufacturers' instructions.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Site-Selective Regulation of Platelet-Derived Growth Factor β Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase

Persson

Sävenhed

Bourdeau

et al. 2004

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

The platelet-derived growth factor (PDGF) ␤ receptor mediates mitogenic and chemotactic signals. Like other tyrosine kinase receptors, the PDGF ␤ receptor is negatively regulated by protein tyrosine phosphatases (PTPs). To explore whether T-cell PTP (TC-PTP) negatively regulates the PDGF ␤ receptor, we compared PDGF ␤ receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos. PDGF ␤ receptors were hyperphosphorylated in TC-PTP ko embryos. Fivefold-higher ligand-induced receptor phosphorylation was observed in TC-PTP ko mouse embryo fibroblasts (MEFs) as well. Reexpression of TC-PTP partly abolished this difference. As determined with site-specific phosphotyrosine antibodies, the extent of hyperphosphorylation varied among different autophosphorylation sites. The phospholipase C␥1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase C␥1 activity and migratory hyperresponsiveness to PDGF. PDGF ␤ receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTP ko MEFs was also higher than that in control cells. This increase occurred with a site distribution different from that seen after TC-PTP depletion. PDGF-induced migration was not increased in PTP-1B ko cells. In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF ␤ receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.Protein tyrosine phosphatases (PTPs) are natural receptor tyrosine kinase antagonists and serve as regulators of both nonreceptor and receptor tyrosine kinases (28,29). Recent investigations indicated that each receptor tyrosine kinase associates with and is dephosphorylated by a number of tyrosine phosphatases. The dephosphorylation of the receptor by individual PTPs can be general, thereby terminating receptor signaling. Alternatively, PTPs can site selectively dephosphorylate a subset of tyrosine residues and thereby modulate signaling downstream of the receptor. By regulating the expression and activation of tyrosine phosphatases, the cell consequently might be able to modulate signaling through receptor tyrosine kinases and fine-tune its response.Platelet-derived growth factors (PDGFs) are a family of growth factors that stimulate cell growth, survival, and motility. PDGF isoforms act by binding to two structurally related protein tyrosine kinases, the PDGF ␣ and ␤ receptors (16). The binding of PDGF to its receptors results in receptor dimerization, promoting phosphorylation in trans between the two receptors in the complex. PDGF-AA forms ␣␣ receptor dimers, PDGF-AB forms ␣␣ and ␣␤ receptor dimers, and PDGF-BB forms all combinations of receptor dimers. Two more PDGF dimers, PDGF-CC and PDGF-DD, recently were identified (2, 24, 25) and shown to preferentially signal through ␣␣ receptor and ␤␤ receptor dimers, respectively, but also may activate both receptor ty...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Site-Selective Regulation of Platelet-Derived Growth Factor β Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase

Persson

Sävenhed

Bourdeau

et al. 2004

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, our results indicate a greater PDGF-dependent increase in Shp-2 phosphorylation compared with other targets in the cells expressing tTG. Furthermore, Shp-2 regulates PDGFR signaling by acting as a sensor of cell-matrix interactions (2,23,24), and cell surface tTG enhances cell-ECM adhesion. Finally, forced Shp-2 targeting to lipid rafts, the membrane domains in which tTG is present (25,26) and integrins and PDGFR accumulate, promotes cell adhesion, and spreading and activates focal adhesion kinase and RhoA (27), all reported features of tTG overexpression phenotype (13).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase

Zemskov¹,

Loukinova²,

Mikhailenko³

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

A functional collaboration between growth factor receptors such as platelet derived growth factor receptor (PDGFR) and integrins is required for effective signal transduction in response to soluble growth factors. However, the mechanisms of synergistic PDGFR/integrin signaling remain poorly understood. Our previous work showed that cell surface tissue transglutaminase (tTG) induces clustering of integrins and amplifies integrin signaling by acting as an integrin binding adhesion coreceptor for fibronectin. Here we report that in fibroblasts tTG enhances PDGFR-integrin association by interacting with PDGFR and bridging the two receptors on the cell surface. The interaction between tTG and PDGFR reduces cellular levels of the receptor by accelerating its turnover. Moreover, the association of PDGFR with tTG causes receptor clustering, increases PDGF binding, promotes adhesion-mediated and growth factor-induced PDGFR activation, and up-regulates downstream signaling. Importantly, tTG is required for efficient PDGF-dependent proliferation and migration of fibroblasts. These results reveal a previously unrecognized role for cell surface tTG in the regulation of the joint PDGFR/integrin signaling and PDGFR-dependent cell responses. Adhesion of cells to the extracellular matrix (ECM)2 regulates a wide range of cellular processes, including cell survival, growth, migration, and differentiation. A central paradigm in the field entails both physical association and functional collaboration between integrins and growth factor receptors (GFRs) in the regulation of cell responses to the ECM and soluble growth factors (1). In particular, the engagement of ␤1 and ␣v␤3 integrins with ECM ligands transiently activates plateletderived growth factor (PDGF) receptor-tyrosine kinase even in

show abstract

“…For example, expression of spry genes in Drosophila and mouse embryos is largely confined to FGF signaling centers (Hacohen et al, 1998;Minowada et al, 1999). In RTK signaling processes where Spry proteins are not expressed, Csw/SHP-2 must stimulate signaling by dephosphorylating other substrates, such as the autophosphorylation site on EGFR and Torso/PDGFRs that recruits RasGAP (Cleghon et al, 1998;Ekman et al, 2002;Agazie and Hayman, 2003b) or sites on Src kinase regulators (Ren et al, 2004;Zhang et al, 2004). In some pathways, such as the Torso pathway, more than one Csw/SHP-2 substrate is likely to be present and regulated by the enzyme (Cleghon et al, 1998;Casci et al, 1999).…”

Section: G547ementioning

confidence: 99%

“…One is the phosphotyrosines on Torso, PDGFR and EGFR that mediate binding and signal inhibition by RasGAP (Cleghon et al, 1998;Ekman et al, 2002;Agazie and Hayman, 2003b). The other is the CSKbinding proteins Paxillin and PAG/Cbp, dephosphorylation of which prevent CSK-mediated inactivation of Src kinase activity and its positive effect on RTK signaling (Ren et al, 2004;Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases

et al. 2006

View full text Add to dashboard Cite

, §Drosophila Corkscrew protein and its vertebrate ortholog SHP-2 (now known as Ptpn11) positively modulate receptor tyrosine kinase (RTK) signaling during development, but how these tyrosine phosphatases promote tyrosine kinase signaling is not well understood. Sprouty proteins are tyrosine-phosphorylated RTK feedback inhibitors, but their regulation and mechanism of action are also poorly understood. Here, we show that Corkscrew/SHP-2 proteins control Sprouty phosphorylation and function. Genetic experiments demonstrate that Corkscrew/SHP-2 and Sprouty proteins have opposite effects on RTK-mediated developmental events in Drosophila and an RTK signaling process in cultured mammalian cells, and the genes display dose-sensitive genetic interactions. In cultured cells, inactivation of SHP-2 increases phosphorylation on the critical tyrosine of Sprouty 1. SHP-2 associates in a complex with Sprouty 1 in cultured cells and in vitro, and a purified SHP-2 protein dephosphorylates the critical tyrosine of Sprouty 1. Substrate-trapping forms of Corkscrew bind Sprouty in cultured Drosophila cells and the developing eye. These results identify Sprouty proteins as in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases and show how Corkscrew/SHP-2 proteins can promote RTK signaling by inactivating a feedback inhibitor. We propose that this double-negative feedback circuit shapes the output profile of RTK signaling events.

show abstract

SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor

Cited by 41 publications

References 33 publications

Site-Selective Regulation of Platelet-Derived Growth Factor β Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase

Site-Selective Regulation of Platelet-Derived Growth Factor β Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase

Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase

Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases

Contact Info

Product

Resources

About