Janus kinase (JAK)-dependent activation of the rho-module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. However, the signaling events linking JAKs to rho small GTPases activation by chemokines is still incompletely described. Here we show that SOS1, ARHGEF1 and DOCK2 guanine nucleotide exchange factors (GEF) mediate CXCL12-induced LFA-1 activation in human primary T lymphocytes. Down-regulated expression of SOS1, ARHGEF1 and DOCK2 impairs LFA-1-mediated rapid T-lymphocyte adhesion as well as underflow arrest on ICAM-1 induced by CXCL12. Moreover, LFA-1 affinity triggering by CXCL12 is impaired by SOS1, ARHGEF1 and DOCK2 down-regulation. Notably, the three GEFs are all critically involved in chemokine-induced RhoA and Rac1 activation, thus suggesting the occurrence of a SOS1 specificity shift in the context of chemokine signaling. Accordingly, SOS1, ARHGEF1 and DOCK2 are tyrosine phosphorylated upon chemokine signaling with timing coherent with rapid LFA-1 affinity activation. Importantly, chemokine-induced tyrosine phosphorylation of these GEFs is fully mediated by JAKs PTKs. Unexpectedly, and differently from VAV1, tyrosine phosphorylation of SOS1, ARHGEF1 and DOCK2, is completely inhibited by PTx pre-treatment, thus suggesting different routes of rho-GEFs triggering upon CXCR4-engagement. Taken together, these findings reveal a deeper level of complexity in the rho-signaling module, with at least four different rho-GEFs cooperating to the regulation of chemokine-induced integrin activation, possibly suggesting the emergence of stochastic concurrency in signaling mechanisms controlling leukocyte trafficking.

SOS1, ARHGEF1 and DOCK2 rho-GEFs mediate JAK-dependent LFA-1 activation by chemokines

TOFFALI, Lara;MONTRESOR, Alessio;Mirenda, Michela;LAUDANNA, Carlo
2016

Abstract

Janus kinase (JAK)-dependent activation of the rho-module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. However, the signaling events linking JAKs to rho small GTPases activation by chemokines is still incompletely described. Here we show that SOS1, ARHGEF1 and DOCK2 guanine nucleotide exchange factors (GEF) mediate CXCL12-induced LFA-1 activation in human primary T lymphocytes. Down-regulated expression of SOS1, ARHGEF1 and DOCK2 impairs LFA-1-mediated rapid T-lymphocyte adhesion as well as underflow arrest on ICAM-1 induced by CXCL12. Moreover, LFA-1 affinity triggering by CXCL12 is impaired by SOS1, ARHGEF1 and DOCK2 down-regulation. Notably, the three GEFs are all critically involved in chemokine-induced RhoA and Rac1 activation, thus suggesting the occurrence of a SOS1 specificity shift in the context of chemokine signaling. Accordingly, SOS1, ARHGEF1 and DOCK2 are tyrosine phosphorylated upon chemokine signaling with timing coherent with rapid LFA-1 affinity activation. Importantly, chemokine-induced tyrosine phosphorylation of these GEFs is fully mediated by JAKs PTKs. Unexpectedly, and differently from VAV1, tyrosine phosphorylation of SOS1, ARHGEF1 and DOCK2, is completely inhibited by PTx pre-treatment, thus suggesting different routes of rho-GEFs triggering upon CXCR4-engagement. Taken together, these findings reveal a deeper level of complexity in the rho-signaling module, with at least four different rho-GEFs cooperating to the regulation of chemokine-induced integrin activation, possibly suggesting the emergence of stochastic concurrency in signaling mechanisms controlling leukocyte trafficking.
Immunology
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/955168
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