The role of protein tyrosine phosphatase alpha tyrosine 789 phosphorylation in integrin signaling
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Sun, Guobin
issued: 2013-02-14T20:40:58Z
issued: 2013
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: 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.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/43924
note: THE ROLE OF PROTEIN TYROSINE PHOSPHATASE ALPHA TYROSINE 789 PHOSPHORYLATION IN INTEGRIN SIGNALING by Guobin Sun B.Sc., Nankai University, 1999 M.Sc., Simon Fraser University, 2006 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2013 © Guobin Sun, 2013 ii Abstract 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 disr…
has type: Thesis/Dissertation
date issued: 2013-05
is shown at: 10.14288/1.0073577
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivs 3.0 Unported
rights URI: http://creativecommons.org/licenses/by-nc-nd/3.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/43924