Glycerophosphoinositol-4-phosphate enhances SDF-1alpha-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.
Patrussi
Laura
L
Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
Mariggio'
Stefania
S
Paccani
Silvia Rossi
SR
Capitani
Nagaja
N
Zizza
Pasquale
P
Corda
Daniela
D
Baldari
Cosima T
CT
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects*; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007295:Inositol Phosphates; D051567:Proto-Oncogene Proteins c-vav; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C496618:VAV1 protein, human; C062528:glycero-3-phosphoinositol 4-phosphate; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases