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IFN-γ is a pleiotropic cytokine importantly involved in the development of skin inflammatory responses. Epidermal keratinocytes are extremely susceptible to IFN-γ action, but, once transduced with the suppressors of cytokine signaling (SOCS)I molecule, they can no longer express a number of IFN-γ inducible signal transducer and activator of transcription (STAT)1-dependent genes. Extracellular-signal-regulated kinase (ERK)1/2 pathway is also involved in the protection of keratinocytes from the proinflammatory effect of IFN-% Here we show that, after IFN-γ stimulation, SOCS1 inhibited IFN-γ receptor and STAT1 phosphorylation but maintained ERK1/2 activation. SOCS1 was also necessary for the IFN-γ-induced RAS and Raf-1 activities in keratinocytes. The enhanced ERK1/2 pathway in SOCS1-overexpressing keratinocytes was in part responsible for their inability to respond to IFN-γ, in terms of CXCL10 and CCL2 production, and for the high production of CXCL8. Moreover, SOCS1 interacted with the RAS inhibitor p120 RasGAP and promoted its degradation after IFN-γ stimulation. We hypothesize that SOCS1 functions as suppressor of IFN-γ signaling, not only by inhibiting STAT1 activation but also by sustaining ERK1/2-dependent antiinflammatory pathways. [ABSTRACT FROM AUTHOR]

Eph receptor tyrosine kinases regulate the spatial organization of cells within tissues. Central to this function is their ability to modulate cell shape and movement in response to stimulation by the ephrin ligands. The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility. Here, we further characterize the role of R-Ras downstream of both EphA and EphB receptors. Our data show that besides inhibiting R-Ras function through phosphorylation, Eph receptors can reduce R-Ras activity through the GTPase-activating protein, p120RasGAP. By using R-Ras mutants that cannot be inactivated by p120RasGAP and/or cannot be phosphorylated at tyrosine 66, we show that the two forms of R-Ras negative regulation - through increased GTP hydrolysis and phosphorylation - differentially contribute to various ephrin-mediated responses. Retraction of the COS cell periphery depends only on R-Ras inactivation through p120RasGAP. By contrast, both reduced R-Ras GTP levels and tyrosine 66 phosphorylation contribute to the ephrin inhibitory effects on COS cell migration and to ephrin-dependent growth cone collapse in primary neurons. Therefore, Eph receptors can regulate R-Ras in two different ways to achieve cell repulsion. [ABSTRACT FROM AUTHOR]