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Blood, 1 February 2001, Vol. 97, No. 3, pp. 608-615
CHEMOKINES
SHP2 and cbl participate in  -chemokine receptor
CXCR4-mediated signaling pathways
Rebecca D. Chernock,
Rama
P. Cherla, and
Ramesh K. Ganju
From the Divisions of Experimental Medicine and
Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA.
Stromal cell-derived factor (SDF)-1 and its receptor, CXCR4,
play an important role in cell migration, embryonic development, and
human immunodeficiency virus infection. However, the cellular signaling
pathways that mediate these processes are not fully elucidated. We and
others have shown that the binding of SDF-1 to CXCR4 activates
phosphatidylinositol-3 kinase (PI-3 kinase), p44/42 mitogen-associated
protein kinase, and the transcription factor nuclear factor- B, and
it also enhances the tyrosine phosphorylation and association of
proteins involved in the formation of focal adhesions. In this study,
we examined the role of phosphatases in CXCR4-mediated signaling
pathways. We observed significant inhibition of SDF-1-induced
migration by phosphatase inhibitors in CXCR4-transfected pre-B lymphoma
L1.2 cells, Jurkat T cells, and peripheral blood lymphocytes. Further
studies revealed that SDF-1 stimulation induced robust tyrosine
phosphorylation in the SH2-containing phosphatase SHP2. SHP2 associated
with the CXCR4 receptor and the signaling molecules SHIP, cbl, and fyn. Overexpression of wild-type SHP2 increased SDF-1-induced
chemotaxis. Enhanced activation of fyn and lyn kinases and the tyrosine
phosphorylation of cbl were also observed. In addition, SDF-1
stimulation enhanced the association of cbl with PI-3 kinase, Crk-L,
and 14-3-3 proteins. Our results suggest that CXCR4-mediated
signaling is regulated by SHP2 and cbl, which collectively participate
in the formation of a multimeric signaling complex.
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