The definitive proof that the kinase activity of HPK1 negatively regulates T cell activation came when two independently-derived lines of genetically modified mice – the catalytically-inactive K46M and K46E HPK1 point mutants – were assessed for their ability to respond to activation signals: by antibody-mediated TCR-crosslinking, by immunization with model antigens and as well as by in vivo tumor challenge (Liu et al., 2019; Hernandez et al., 2018). The gene discussed is MAP4K1; the disease is neoplasm.