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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.
Author: | Helga Schneider, Hongyan Wang, Monika RaabORCiD, Elke Valk, Xin Smith, Matt Lovatt, Zhonglin Wu, Braudel Maqueira-Iglesias, Klaus StrebhardtORCiDGND, Christopher E. Rudd |
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URN: | urn:nbn:de:hebis:30-57784 |
DOI: | https://doi.org/10.1371/journal.pone.0001718 |
ISSN: | 1932-6203 |
Parent Title (English): | PLoS One |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2008/03/05 |
Date of first Publication: | 2008/03/05 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2008/09/25 |
Volume: | 3 |
Issue: | (3): e1718 |
Note: | 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 |
HeBIS-PPN: | 205844103 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Licence (German): | Creative Commons - Namensnennung 3.0 |