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The regulation and function of protein tyrosine phosphatase alpha (PTPα) tyrosine phosphorylation

University of British Columbia

Protein tyrosine phosphatase alpha (PTPα) is a ubiquitously expressed receptor protein tyrosine phosphatase that functions as an early upstream regulator in the integrin signaling pathway. The integrins, by interacting with extracellular matrix components, regulate cell growth, migration, and survival, and are functionally linked to multiple aspects of cancer biology such as invasion and metastasis. PTPα plays a major role in the integrin signaling cascade by activating Src family kinases (SFKs), which are required for the full activation of the central signaling molecule focal adhesion kinase (FAK). The importance of PTPα in integrin signaling is demonstrated by defects observed in integrin-mediated cytoskeletal rearrangement and focal adhesion formation in PTPα-deficient fibroblasts. PTPα contains a tyrosine phosphorylation site, Tyr-789, located in the intracellular C-terminal tail. Tyr-789 phosphorylation is shown to not affect PTPα catalytic activity, but allows binding of Src and the adaptor protein Grb2. Little is known about the regulation and function of PTPα Tyr-789 phosphorylation. Recent work from our laboratory has discovered that PTPα Tyr-789 phosphorylation is positively regulated upon integrin engagement and is functionally required for integrin-induced cytoskeletal reorganization events, suggesting the importance of the phospho-Tyr-789 motif in PTPα-mediated signaling events. In a search for other regulators of PTPα Tyr-789 phosphorylation, IGF-1, and potentially aFGF, LPA, and PMA, were found to positively regulate PTPα Tyr-789 phosphorylation. These inductions occurred in a Src/Fyn/Yes-independent manner, indicating an involvement of likely non-SFK cellular kinases distinct from those involved in integrin-induced PTPα phosphorylation. Although PTPα Tyr-789 phosphorylation mediates integrin-induced cytoskeletal remodeling, this phosphorylation event did not appear to act upstream of the Rho family of small GTPases that are key regulators of cellular actin structures. To further understand the precise action of PTPα Tyr-789 phosphorylation in integrin (and other) signaling pathway, the interaction between the PTPα phospho-Tyr-789 motif and other cellular proteins was investigated. Integrin-induced PTPα Tyr-789 phosphorylation was accompanied by increased Grb2 recruitment to phospho-PTPα which provides for a mechanism by which Grb2-interacting signaling proteins are recruited to PTPα to mediate downstream integrin signaling events. In addition, several proteins representing potential PTPα phospho-Y789 interacting proteins were isolated by (phospho)peptide affinity purification. The identification of these proteins and validation of their interactions with PTPα may reveal the precise signaling role of PTPα Tyr-789 phosphorylation.

Text

2011-02-22

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http://hdl.handle.net/2429/31583

Pathology

University of British Columbia

Graduate