Hematopoietic progenitor kinase 1 and Receptor tyrosine kinases (HPK1 and RTKs)

Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the Ste20-like serine/threonine kinase family primarily expressed in hematopoietic cells, where it functions as a negative regulator of T-cell receptor (TCR) signaling and overall immune cell activation (UniProt, 2023). Receptor tyrosine kinases (RTKs) are a broad class of high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones, including well-known members like EGFR, VEGFR, and PDGFR (NIH, 2022). While RTKs are typically transmembrane proteins that drive cell growth and survival, HPK1 is an intracellular kinase that modulates the immune system's ability to recognize and attack tumor cells. This entry is considered heterogeneous as it combines a specific intracellular kinase with a broad family of cell-surface receptors. In oncology, HPK1 is targeted to reverse T-cell exhaustion and enhance anti-tumor immunity, whereas RTKs are targeted to directly inhibit oncogenic signaling and tumor angiogenesis (PubMed, 2021). Small-molecule inhibitors are the primary therapeutic modality for both, often designed to bind the ATP-binding pocket of the kinase domain to halt downstream signal transduction.

Other names

MAP4K1Mitogen-activated protein kinase kinase kinase kinase 1Protein tyrosine kinasesTransmembrane receptor protein tyrosine kinases

Inhibition of kinase catalytic activity by competing with ATP binding, thereby preventing the phosphorylation of downstream substrates and blocking signaling cascades such as the MAPK/ERK and PI3K/AKT pathways.