The CXC chemokine stromal cell-derived factor activates a G(i)-Coupled phosphoinositide 3-kinase in T lymphocytes

The cellular effects of stromal cell-derived factor-1 (SDF-1) are mediated primarily by binding to the CXC chemokine receptor-4, We report in this stu dy that SDP-1 and its peptide analogues induce a concentration- and tine-de pendent accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns( 3,4,5)P-3) in Jurkat cells. This SDF-1-stimulated generation of D-3 phospho inositide lipids was inhibited by pretreatment of the cells with an SDF-1 p eptide antagonist or an anti-CXCR4 Ab, In addition, the phosphoinositide 3 (PX 3)-kinase inhibitors wortmannin and LY294002, as well as the Gi protein inhibitor pertussis toxin, also inhibited the SDF-1-stimulated accumulatio n of PtdIns(3,4,5)P-3. The effects of SDP-1 on D-3 phosphoinositide lipid a ccumulation. correlated web with activation of the known PI 3-kinase effect or protein kinase B, which was also inhibited by wortmannin and pertussis t oxin, Concentrations of PI 3-kinase inhibitors, sufficient to inhibit PtdIn s(3,4,5)P-3 accumulation, also inhibited chemotaxis of Jurkat and periphera l blood-derived T lymphocytes in response to, SDF-1, In contrast, SDP-I-sti mulated actin polymerization was only partially inhibited by PI 3-kinase in hibitors, suggesting that while chemotaxis is fully dependent on PI 3-kinas e activation, actin polymerization requires additional biochemical inputs. Finally, SDF-1-stimulated extracellular signal-related kinase (ERK)-1/2 mit ogen-activated protein kinase activation was inhibited by PI 3-kinase inhib itors. In addition, the mitogen-activated protein/ERK kinase inhibitor PD09 8059 partially attenuated chemotaxis in response to SDF-1. Hence, it appear s that EPK1/2 activation is dependent on PI 3-kinase activation, and both b iochemical events are involved in the regulation of SDF-1-stimulated chemot axis.