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Adaptor SKAP-55 binds p21 activating exchange factor RasGRP1 and negatively regulates the p21-ERK pathway in T-cells.

Authors :
Helga Schneider
Hongyan Wang
Monika Raab
Elke Valk
Xin Smith
Matt Lovatt
Zhonglin Wu
Braudel Maqueira-Iglesias
Klaus Strebhardt
Christopher E Rudd
Source :
PLoS ONE, Vol 3, Iss 3, p e1718 (2008)
Publication Year :
2008
Publisher :
Public Library of Science (PLoS), 2008.

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
3
Issue :
3
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.37259dd77d584d01acbbb8de150e22af
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0001718