| First Author | Schneider H | Year | 2008 |
| Journal | PLoS One | Volume | 3 |
| Issue | 3 | Pages | e1718 |
| PubMed ID | 18320039 | Mgi Jnum | J:133130 |
| Mgi Id | MGI:3777847 | Doi | 10.1371/journal.pone.0001718 |
| Citation | Schneider H, et al. (2008) Adaptor SKAP-55 Binds p21 Activating Exchange Factor RasGRP1 and Negatively Regulates the p21-ERK Pathway in T-Cells. PLoS One 3(3):e1718 |
| abstractText | 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. |
