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The role of protein tyrosine phosphatase alpha tyrosine 789 phosphorylation in integrin signaling

University of British Columbia

Focal adhesions (FA) form interfaces between the extracellular matrix and the cytoskeleton to regulate cell responses such as cell proliferation, survival, and migration. The functions and dynamic interactions of many of the ~180 molecules in this integrin-initiated FA complex network are far from fully understood. Among these is the receptor-like protein tyrosine phosphatase PTPα. In addition to the integrin-proximal action of PTPα to catalyze activation of Src family kinases, subsequent phosphorylation of PTPα at its C-terminal Tyr789 site is essential and acts in an unknown manner to promote cell spreading and migration. We used reconstitution assays in PTPα-null cells to identify and distinguish integrin signaling events that were PTPα-dependent and PTPα-Tyr789-dependent. Results show that PTPα-Tyr789 mediates the localization of PTPα and the scaffolding protein Cas to FAs where Cas interacts with and gets phosphorylated by Src to initiate Cas/Crk-Rac/Cdc42-PAK signaling. Linking these events, this study identifies the Cas-binding protein BCAR3 as a molecular connector of PTPα and Cas, with phosphoTyr789-PTPα interacting with the BCAR3 SH2 domain to recruit BCAR3-Cas to newly forming adhesion sites. These findings identify phospho-Tyr789-PTPα as the first cellular ligand for the SH2 domain of BCAR3, and reveal a role of PTPα in integrin-induced adhesion complex assembly that enables Src-mediated activation of the pivotal function of Cas in cell migration. Furthermore I extended this study into a cancer cell model by showing that the disruption of this PTPα-BCAR3-Cas-Src signaling module inhibits the invasive motility in a rhabdomyosarcoma cell line. In summary, my results in this thesis elucidate the molecular mechanism underlying the PTPα-Tyr789-dependent cell spreading and migration, and support that the PTPα-BCAR3-Cas complex is a critical regulator of cell migration as well as cancer cell invasion and metastasis.

Text

2013-02-14

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/43924

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/