Functional interactions of HPK1 with adaptor proteins

Abstract

Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a hematopoietic-specific mammalian STE20-like protein serine/threonine kinase, comprised of a STE20-like kinase domain in its N-terminus, four proline-rich motifs, a caspase cleavage site, and a distal C-terminal Citron homology domain. HPK1 is involved in many cellular signaling cascades that include MAPK signaling, antigen receptor signaling, apoptosis, growth factor signaling, and cytokine signaling. HPK1 binds many adaptor proteins including members of the Grb2 family, Nck family, Crk family, SLP-76 family, and actin-binding adaptors like HIP-55. HPK1 tyrosine phosphorylation and kinase activation depend on the presence of adaptor proteins. Adaptor proteins are required not only for linking HPK1 to cell surface receptors like the EGFR, but also for downstream gene transcription like NFAT, AP-1 and IL-2. The HPK1 association with Crk, CrkL, and HIP-55 mediate HPK1-dependent c-Jun N-terminal kinase (JNK) activation, while the association of HPK1 with SLP-76, Gads, CrkL, Grb2, and Grap affect T- and B-cell dependent gene transcription. Interestingly, HPK1 has been implicated in both increasing and decreasing NFAT, AP-1, and IL-2 gene transcription in T-cells where adaptor proteins play a key role. Lastly, HPK1 will phosphorylate Crk and CrkL, in vitro, which presents a novel possibility for the regulation of adaptor proteins and downstream signaling events.