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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1730-1738.
Prepublished online as a Blood First Edition Paper on May 30, 2007; DOI 10.1182/blood-2007-01-068411.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells
Laura Patrussi1,
Cristina Ulivieri1,
Orso Maria Lucherini1,
Silvia Rossi Paccani1,
Alessandra Gamberucci2,
Luisa Lanfrancone3,
Pier Giuseppe Pelicci3, and
Cosima T. Baldari1
Departments of1 Evolutionary Biology and
2 Physiopathology, University of Siena, Siena;
3 Department of Molecular Oncology, European Institute of Oncology, Milan, Italy
ShcA is an important mediator of Ras/MAPK activation in PTK-regulated pathways triggered by surface receptors. This function is subserved by the constitutively expressed p52-kDa isoform. Besides activating Ras, p52Shc couples the TCR to Rho GTPases, and thereby participates in actin cytoskeleton remodeling in T cells. Here we have addressed the potential involvement of p52Shc in T-cell chemotaxis and the role of the phosphorylatable tyrosine residues, YY239/240 and Y317, in this process. We show that CXCR4 engagement by the homeostatic chemokine, SDF-1 , results in p52Shc phosphorylation and its assembly into a complex that includes Lck, ZAP-70, and Vav. This process was found to be both Lck and Gi dependent. Expression of p52Shc mutants lacking YY239/240 or Y317, or p52Shc deficiency, resulted in a profound impairment in CXCR4 signaling and SDF-1–dependent chemotaxis, underscoring a crucial role of p52Shc as an early component of the CXCR4 signaling cascade. p52Shc was also found to be required for ligand-dependent CXCR4 internalization independently of tyrosine phosphorylation. Remarkably, CXCR4 engagement promoted phosphorylation of the  chain of the TCR/CD3 complex, which was found to be essential for CXCR4 signaling, as well as for SDF-1–dependent receptor endocytosis and chemotaxis, indicating that CXCR4 signals by transactivating the TCR.
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