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A more recent version of this article appeared on February 1, 2004
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Submitted on September 24, 2003
Revised on October 30, 2003
Accepted on October 31, 2003
1 Dipartimento di Genetica, Biologia e Biochimica, Via Santena 5 bis, 10126 Torino, Italy; these authors equally contributed to this work
2 Dipartimento di Genetica, Biologia e Biochimica, Via Santena 5 bis, 10126 Torino, Italy
3 Consiglio Nazionale delle Ricerche, CSAAPZ, Bioindustry Park del Canavese, Colleretto Giacosa, Torino
* Corresponding author. E-mail address: paola.defilippi{at}unito.it.
Integrin-mediated cell adhesion stimulates a cascade of signaling pathways that control cell proliferation, migration and survival, mostly through tyrosine phosphorylation of signaling molecules. p130Cas, originally identified as a major substrate of v-Src, is a scaffold molecule which interacts with several proteins and mediates multiple cellular events following cell adhesion and mitogen treatment.
Here we describe a novel p130Cas-associated protein named p140Cap (Cas associated protein) as a new tyrosine phosphorylated molecule involved in integrin- and EGF-dependent signaling.
By affinity chromatography of human ECV304 cell extracts on a MBP-p130Cas column followed by mass spectrometry Maldi-TOF analysis, we identified p140Cap as a protein migrating at 140 kDa. We detected its expression in human, mouse and rat cells and in different mouse tissues. Endogenous and transfected p140Cap proteins coimmunoprecipitate with p130Cas in ECV304 and in HEK293 cells and associate with p130Cas through their carboxy-terminal region. By immunofluorescence analysis we demonstrated that in ECV304 cells plated on fibronectin, the endogenous p140Cap colocalizes with p130Cas in the perinuclear region as well as in lamellipodia. In addition p140Cap codistributes with cortical actin and actin stress fibers but not with focal adhesions. We also show that p140Cap is tyrosine phosphorylated within 15 min of cell adhesion to integrin ligands. p140Cap tyrosine phosphorylation is also induced in response to EGF through an EGF-Receptor (EGFR) dependent-mechanism. Interestingly expression of p140Cap in NIH3T3 and in ECV304 cells delays the onset of cell spreading in the early phases of cell-adhesion to fibronectin. Therefore p140Cap is a novel protein associated with p130Cas and actin cytoskeletal structures. Its tyrosine phosphorylation by integrin-mediated adhesion and EGF stimulation and its involvement in cell spreading on matrix proteins suggest that p140Cap plays a role in controlling actin cytoskeleton organization in response to adhesive and growth factor signaling.
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