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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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Submitted January 17, 2007
Accepted May 29, 2007
p52SHC is required for CXCR4-dependent signaling and chemotaxis in T-cells
Laura Patrussi, Cristina Ulivieri, Orso Maria Lucherini, Silvia Rossi Paccani, Alessandra Gamberucci, Luisa Lanfrancone, Pier Giuseppe Pelicci, and Cosima T Baldari*
Department of Evolutionary Biology, University of Siena, Siena, Italy
Department of Physiopathology, University of Siena, Siena, Italy
Department of Molecular Oncology, European Institute of Oncology, Milan, Italy
* Corresponding author; email: baldari{at}unisi.it.
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 to 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 which 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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