Adaptor SKAP-55 binds p21ras activating exchange factor RasGRP1 and negatively regulates the p21ras-ERK pathway in T-Cells

  • 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 p21ras 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 p21ras -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 p21ras activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21ras 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 p21ras becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21ras-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion.

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Author:Helga Schneider, Hongyan Wang, Monika RaabORCiD, Elke Valk, Xin Smith, Matt Lovatt, Zhonglin Wu, Braudel Maqueira-Iglesias, Klaus StrebhardtORCiD, Christopher E. Rudd
Parent Title (English):PLoS One
Document Type:Article
Date of Publication (online):2008/03/05
Date of first Publication:2008/03/05
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2008/09/25
Issue:(3): e1718
Copyright Schneider et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source:PLoS ONE. 2008; 3(3): e1718. Published online 2008 March 5. doi: 10.1371/journal.pone.0001718
Institutes:Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Licence (German):License LogoCreative Commons - Namensnennung 3.0