Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related serine/ threonine protein kinase, is a hematopoietic-specific upstream activator of the c-Jun N-terminal kinase. Here, we provide evidence to demonstrate the involvement of HPK1 in T cell receptor (TCR) signaling. HPK1 was activated and tyrosine-phosphorylated with similar kinetics following TCR/CD3 or perv anadate stimulation. Co-expression of protein-tyrosine kinases, Lck and Zap 70, with HPK1 led to HPK1 activation and tyrosine phosphorylation in transf ected mammalian cells. Upon TCR/CD3 stimulation, HPK1 formed inducible comp lexes with the adapters Nck and Grk with different kinetics, whereas it con stitutively interacted with the adapters Grb2 and CrkL in Jurkat T cells. I nterestingly, HPK1 also inducibly associated with linker for activation of T cells (LAT) through its proline-rich motif and translocated into glycolip id-enriched microdomains (also called lipid rafts) following TCR/CD3 stimul ation, suggesting a critical role for LAT in the regulation of HPK1, Togeth er, these results identify HPK1 as a new component of TCR signaling. T cell -specific signaling molecules Lck, Zap70, and LAT play roles in the regulat ion of HPK1 during TCR signaling. Differential complex formation between HP K1 and adapters highlights the possible involvement of HPK1 in multiple sig naling pathways in T cells.