A phosphotyrosine displacement mechanism for activation of Src by PTPα

Department of Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
The EMBO Journal (Impact Factor: 10.75). 03/2000; 19(5):964-78.
Source: PubMed

ABSTRACT Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells. pTyr789 in PTPalpha is constitutively phosphorylated and binds Grb2, an interaction that may inhibit PTPalpha activity. We show here that this phosphorylation also specifically enables PTPalpha to dephosphorylate pTyr527. Tyr789-->Phe mutation abrogates PTPalpha-Src binding, dephosphorylation of pTyr527 (although not of other substrates), and neoplastic transformation by overexpressed PTPalpha in vivo. We suggest that pTyr789 enables pTyr527 dephosphorylation by a pilot binding with the Src SH2 domain that displaces the intramolecular pTyr527-SH2 binding. Consistent with model predictions, we find that excess SH2 domains can disrupt PTPalpha-Src binding and can block PTPalpha-mediated dephosphorylation and activation in proportion to their affinity for pTyr789. Moreover, we show that, as predicted by the model, catalytically defective PTPalpha has reduced Src binding in vivo. The displacement mechanism provides another potential control point for physiological regulation of Src-family signal transduction pathways.

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    • "However, more remains to be learned about how E-cadherin might activate the RPTPα-SFK pathway. RPTPα can be activated by several mechanisms (den Hertog et al., 1995; Tracy et al., 1995; Zheng et al., 2000), but an interesting clue lies in the capacity for homodimerization to inhibit the catalytic activity of RPTPα. It has been shown recently that disruption of this autoinhibitory mechanism may increase Src activity in a significant subset of colon, breast, and liver human tumors (Huang et al., 2011). "
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    • "RPTPα can be activated by several mechanisms (den Hertog et al., 1995; Tracy et al., 1995; Zheng et al., 2000), but an interesting clue lies in the capacity for homodimerization to inhibit the catalytic activity of RPTPα. It has been shown recently that disruption of this auto-inhibitory mechanism may increase Src activity in significant subset of colon, breast and liver human tumors (Huang et al., 2011). "
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    ABSTRACT: Cell-cell adhesion couples the contractile cortices of epithelial cells together, generating tension to support a range of morphogenetic processes. E-cadherin adhesion plays an active role in generating junctional tension, by promoting actin assembly and cortical signaling pathways that regulate Myosin II. Multiple Myosin II paralogs accumulate at mammalian epithelial cell-cell junctions. Earlier we found that Myosin IIA responds to Rho-ROCK signaling to support junctional tension in MCF-7 cells. Although Myosin IIB is also found at the zonula adherens (ZA) in these cells, its role in junctional contractility, and its mode of regulation, are less well understood. We now demonstrate that Myosin IIB contributes to tension at the epithelial ZA. Further, we identify a RPTPα-SFK-Rap1 pathway as responsible for recruiting Myosin IIB to the ZA and supporting contractile tension. Overall, these findings reinforce the concept that orthogonal E-cadherin-based signaling pathways recruit distinct Myosin II paralogs to generate the contractile apparatus at apical epithelial junctions. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; 26(7). DOI:10.1091/mbc.E14-07-1223 · 4.55 Impact Factor
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    • "servation that exogenously expressed RPTP - α exists pre - dominantly as dimers on the cell surface ( Jiang et al . 2000 ) . PTP activity of RPTP - α is regulated by both tyrosine and serine phosphorylation . RPTP - α is constitutively phosphory - lated on C - terminal tyrosine 789 , which results in enhanced PTP activity toward Src tyrosine 527 ( Zheng et al . 2000 ) . Mutation of tyrosine 789 into a non - phosphorylatable amino acid alters functional properties of RPTP - α ( Lammers et al . 2000 ; Su et al . 1996 ) . Tyrosine 789 - phosphorylated RPTP - α binds the adaptor protein Grb - 2 , which blocks binding of Grb - 2 to Sos , a guanine nucleotide exchange factor needed for Ras activation , r"
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    ABSTRACT: Protein tyrosine phosphorylation is a fundamental regulatory mechanism controlling cell proliferation, differentiation, communication, and adhesion. Disruption of this key regulatory mechanism contributes to a variety of human diseases including cancer, diabetes, and auto-immune diseases. Net protein tyrosine phosphorylation is determined by the dynamic balance of the activity of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Mammals express many distinct PTKs and PTPs. Both of these families can be sub-divided into non-receptor and receptor subtypes. Receptor protein tyrosine kinases (RPTKs) comprise a large family of cell surface proteins that initiate intracellular tyrosine phosphorylation-dependent signal transduction in response to binding of extracellular ligands, such as growth factors and cytokines. Receptor-type protein tyrosine phosphatases (RPTPs) are enzymatic and functional counterparts of RPTKs. RPTPs are a family of integral cell surface proteins that possess intracellular PTP activity, and extracellular domains that have sequence homology to cell adhesion molecules. In comparison to extensively studied RPTKs, much less is known about RPTPs, especially regarding their substrate specificities, regulatory mechanisms, biological functions, and their roles in human diseases. Based on the structure of their extracellular domains, the RPTP family can be grouped into eight sub-families. This article will review one representative member from each RPTP sub-family.
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Ross J Resnick