Glycerophosphoinositol-4-phosphate enhances SDF-1?-stimulated T-cell chemotaxis through PTK-dependent activation of Vav

Glycerophosphoinositols (GPIs) are water-soluble phosphoinosite metabolites produced by all cell types, whose levels increase in response to a variety of extracellular stimuli, and are particularly high in Ras-transformed cells. GPIs are released to the extracellular space, wherefrom they can be taken up by other cells through a specific transporter. Exogenous GPIs affect a plethora of cellular functions. Among these compounds the most active is GroPIns4P, which affects cAMP levels and PKA-dependent functions through the inhibition of heterotrimeric Gs proteins. GroPIns4P has also recently been found to promote actin cytoskeleton reorganization by inducing Rho and Rac activation through an as yet unidentified mechanism. Here we have assessed the potential effects of GroPIns4P on T-cells. We found that GroPIns4P enhances CXCR4-dependent chemotaxis. This activity results from the capacity of GroPIns4P to activate the Rho GTPase exchange factor, Vav, through an Lck-dependent pathway which also results in activation of the stress kinases JNK and p38. GroPIns4P was also found to activate with a delayed kinetics the Lck-dependent activation of ZAP-70, Shc and Erk1/2. The activities of GroPIns4P were found to be dependent on its capacity to inhibit cAMP production and PKA activation. Collectively, the data provide the first evidence of a role of glycerophosphoinositols as modulators of T-cell signaling and establish a mechanistic basis for the effects of this phosphoinositide derivative on F-actin dynamics.