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

Helga Schneider1, Hongyan Wang, Monika Raab

  • 1Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Plos One
|March 6, 2008
PubMed

Insights

The adaptor SKAP-55 regulates T-cell adhesion and the p21(ras)-ERK pathway. Loss of SKAP-55 causes defective adhesion but hyper-activated ERK signaling, mediated by RasGRP1.

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • The adaptor protein SKAP-55 is known to mediate LFA-1 adhesion on T-cells.
  • The role of SKAP-55 in regulating downstream signaling pathways, such as the p21(ras)-ERK pathway, remains unclear.
  • The p21(ras)-ERK pathway is crucial for T-cell function.

Purpose of the Study:

  • To investigate the role of SKAP-55 in regulating T-cell adhesion and the p21(ras)-ERK signaling pathway.
  • To determine if SKAP-55 acts as a node coordinating adhesion with downstream signaling.
  • To elucidate the mechanism by which SKAP-55 influences p21(ras)-ERK activation.

Main Methods:

  • Utilized SKAP-55 deficient primary T-cells and SKAP-55 knockdown T-cell lines.
  • Assessed LFA-1 adhesion and activation of the p21(ras)-ERK pathway.
  • Investigated the interaction between SKAP-55 and RasGRP1 using biochemical assays.
  • Examined the localization of RasGRP1 in trans-Golgi network (TGN) upon T-cell receptor activation.

Main Results:

  • SKAP-55 deficiency led to impaired LFA-1 adhesion and hyper-activation of the ERK pathway.
  • Knockdown of SKAP-55 increased p21(ras) activation, while overexpression inhibited ERK and ELK activation.
  • SKAP-55 directly binds to RasGRP1, and this interaction is essential for inhibiting ERK and ELK activation.
  • Loss of SKAP-55 resulted in increased RasGRP1 presence in the TGN following TCR activation.

Conclusions:

  • SKAP-55 plays a dual role in T-cell signaling, negatively regulating the p21(ras)-ERK pathway.
  • The interaction between SKAP-55 and RasGRP1 is critical for controlling p21(ras) activation.
  • SKAP-55 may restrict p21(ras)-ERK pathway activation during T-cell adhesion to prevent excessive signaling.

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