Adaptor SKAP-55 Binds p21 Activating Exchange Factor RasGRP1 and Negatively Regulates the p21-ERK Pathway in T-Cells.

@article{citeulike:2507686, abstract = {While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21(ras) and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21(ras) -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21(ras) activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21(ras) activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55-/- primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21(ras) becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21(ras)-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion.}, address = {Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.}, author = {Schneider, H. and Wang, H. and Raab, M. and Valk, E. and Smith, X. and Lovatt, M. and Wu, Z. and Maqueira-Iglesias, B. and Strebhardt, K. and Rudd, C. E. }, citeulike-article-id = {2507686}, doi = {http://dx.doi.org/10.1371/journal.pone.0001718}, issn = {1932-6203}, journal = {PLoS ONE}, keywords = {erk, skap55}, number = {3}, posted-at = {2008-03-11 11:41:13}, priority = {2}, title = {Adaptor SKAP-55 Binds p21 Activating Exchange Factor RasGRP1 and Negatively Regulates the p21-ERK Pathway in T-Cells.}, url = {http://dx.doi.org/10.1371/journal.pone.0001718}, volume = {3}, year = {2008} }

TY - JOUR ID - citeulike:2507686 L3 - citeulike-article-id:2507686 TI - Adaptor SKAP-55 Binds p21 Activating Exchange Factor RasGRP1 and Negatively Regulates the p21-ERK Pathway in T-Cells. JF - PLoS ONE VL - 3 IS - 3 AD - Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge, United Kingdom. SN - 1932-6203 N2 - While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21(ras) and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21(ras) -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21(ras) activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21(ras) activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55-/- primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21(ras) becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21(ras)-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion. KW - erk KW - skap55 AU - Schneider, H AU - Wang, H AU - Raab, M AU - Valk, E AU - Smith, X AU - Lovatt, M AU - Wu, Z AU - Maqueira-Iglesias, B AU - Strebhardt, K AU - Rudd, CE PY - 2008/// UR - http://dx.doi.org/10.1371/journal.pone.0001718 ER -