HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion.
The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1). Active Rap1, via its binding to RapL (regulator for cell adhesion and polarization enriched in lymphoid tissues), mediates LFA-1 integrin activation. We show here that HPK1, which also binds SLP-76, compete with ADAP for SLP-76 binding. In addition, HPK1 dampens Rap1 activation, resulting in decreased LFA-1 activity. Analysis of HPK1-deficient T cells revealed increased ADAP recruitment to SLP-76 and elevated Rap1 activation in those cells, leading to increased adhesion to ICAM-1 and cell spreading. Altogether, these results describe a novel function for HPK1 in linking TCR signaling to cell adhesion regulation and provide a mechanistic explanation for the negative regulatory role of HPK1 in T-cell biology.
Max Planck Institute for Molecular Biomedicine, Department of Vascular Cell Biology, Münster, Germany.
Irene M
IM
Patzak
Sebastian
S
Königsberger
Akira
A
Suzuki
Tak W
TW
Mak
Friedemann
F
Kiefer
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell; D020827:rap1 GTP-Binding Proteins; C491468:Fyb protein, mouse; C521189:RIAM protein, mouse; C514255:SKAP1 protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C102102:hematopoietic progenitor kinase 1