SAM68 ASSOCIATION WITH P120GAP IN CD4(-CELLS IS DEPENDENT ON CD4 MOLECULE EXPRESSION() T)

p120 GTPase-activating protein (p120GAP) is a major negative regulator of p21(ras) activity in several cell types including T cells. Catalyt ic activity of this enzyme is regulated in part by its interaction wit h several associated tyrosine-phosphorylated proteins. Sam68 was initi ally described as associated with p120GAP, It has been further establi shed that Sam68 is a substrate of src kinases in mitosis and that it i s not associated with p120GAP in transformed fibroblasts. We describe herein that Sam68 associates with p120GAP and PLC gamma 1 in human mat ure T cells and in a T cell line expressing the CD4 molecule HUT78 CD4 (+). This association is present in nonactivated cells and increases a fter anti-CD3 activation. It is dependent on CD4 expression and, in pa rt, on the association of CD4 with p56(lck), as shown by the strongly decreased association of Sam68 with p120GAP in the CD4(-) mutants, HUT 78 CD4(-), and by the reduced association of Sam68 with both p120GAP a nd p56(lck) in the HUT78 T cell line expressing a CD4 mutant unable to interact with p56(lck), HUT78 C420/22, We propose that recruitment of Sam68, via CD4/p56(lck), to the inner face of the plasma membrane may permit, via its docking properties, the correct association of key si gnaling molecules including PLC gamma 1 and p120GAP, This formation of transduction modules will enable the activation of different signalin g cascades including the p21(ras) pathway and an array of downstream e vents, ultimately leading to T cell activation.