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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.