Protein kinase D1 and the β1 integrin cytoplasmic domain control β1 integrin function via regulation of Rap1 activation

The functional activity of integrins is dynamically regulated by T cell receptor stimulation and by protein kinase C (PKC). We report a novel function for the PKC effector protein kinase D1 (PKD1) in integrin activation. Constitutively active and kinase-inactive PKD1 mutants lacking the PKD1 pleckstrin homology (PH) domain block phorbol ester and TCR-mediated activation and clustering of beta 1 integrins. The PH domain of PKD1 mediates the association of PKD1 with the GTPase Rap1 and is central to Rap1 activation and membrane translocation in T cells. Furthermore, PKD1 and Rap1 associate with beta 1 integrins in a manner that is dependent on the carboxy-terminal end of the beta 1 integrin subunit cytoplasmic domain. beta 1 integrin expression is required for Rapt activation and membrane localization of the PKD1-Rapt complex. Therefore, PKD1 promotes integrin activation in T cells by regulating Rapt activation and membrane translocation via interactions with the beta 1 integrin subunit cytoplasmic domain.