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D120 and K152 within the PH domain of T cell adapter SKAP55 regulate plasma membrane targeting of SKAP55 and LFA-1 affinity modulation in human T lymphocytes.
Witte, Amelie Meineke, Bernhard Sticht, Jana Philipsen, Lars Kuropka, Benno Müller, Andreas J Freund, Christian Schraven, Burkhart Kliche, Stefanie
Witte, Amelie
Meineke, Bernhard
Sticht, Jana
Philipsen, Lars
Kuropka, Benno
Müller, Andreas J
Freund, Christian
Schraven, Burkhart
Kliche, Stefanie
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2017-01-04
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Abstract
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its Pleckstrin Homology (PH) domain. We identified two critical amino acid residues within the PH domain of SKAP55, aspartic acid 120 (D120) and lysine 152 (K152). D120 facilitates retention of SKAP55 in the cytoplasm of non-stimulated T cells while K152 promotes SKAP55 membrane recruitment via Actin binding upon TCR-triggering. Importantly, the K152-dependent interaction of the PH domain with Actin promotes the binding of Talin to LFA-1 thus facilitating LFA-1 activation. These data suggest that K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1.
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D120 and K152 within the PH domain of T cell adapter SKAP55 regulate plasma membrane targeting of SKAP55 and LFA-1 affinity modulation in human T lymphocytes. 2017 Mol. Cell. Biol.
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en
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1098-5549