PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domainAbstract Leucine-rich-repeat-kinase 1 (LRRK1) and its homologue LRRK2 are multidomain kinases possessing a ROC-CORA-CORB containing GTPase domain and phosphorylate distinct Rab proteins. LRRK1 loss of function mutations cause the bone disorder osteosclerotic metaphyseal dysplasia, whereas LRRK2 missense mutations that enhance kinase activity cause Parkinson’s disease. Previous work suggested that LRRK1 but not LRRK2, is activated via a Protein Kinase C (PKC)-dependent mechanism. Here we demonstrate that phosphorylation and activation of LRRK1 in HEK293 cells is blocked by PKC inhibitors including LXS-196 (Darovasertib), a compound that has entered clinical trials. We show multiple PKC isoforms phosphorylate and activate recombinant LRRK1 in a manner reversed by phosphatase treatment. PKCα phosphorylates LRRK1 at a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain that lies at the equivalent region of the LRRK2 DK helix that is reported to stabilize the kinase domain αC-helix in the active conformation. Thr1075 lies within an optimal PKC site phosphorylation motif and its mutation to Ala, blocked PKC-mediated activation of...Access is restricted by the data custodian. The collection's description and structure are public; the data is not available for querying through this network.PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain is published on Viral AI.