Format

Send to

Choose Destination
Blood. 2007 Sep 15;110(6):1730-8. Epub 2007 May 30.

p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells.

Author information

1
Departments of Evolutionary Biology, European Institute of Oncology, Milan, Italy.

Abstract

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-1alpha, 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-1alpha-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 zeta chain of the TCR/CD3 complex, which was found to be essential for CXCR4 signaling, as well as for SDF-1alpha-dependent receptor endocytosis and chemotaxis, indicating that CXCR4 signals by transactivating the TCR.

PMID:
17537990
DOI:
10.1182/blood-2007-01-068411
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center