Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family.

Abstract

Homeodomain-interacting protein kinases including HIPK1, HIPK2 and HIPK3 are serine/threonine kinases that form a family of highly conserved kinases. HIPKs are involved in diverse cellular functions including regulation cell death, survival, proliferation and differentiation. Here we report the characterization of a human HIPK4 that we identified in a proteomic screen during our efforts to unravel novel markers linked to cell death and survival. Human HIPK4 protein is composed of 616 residues with predicted molecular mass of 69.425 kDa and harbors a serine/threonine protein kinase catalytic domain at its N-terminal end. In the in vitro kinase assay, HIPK4 exhibits kinase activity and mutation of the conserved lysine 40 or aspartic acid 136 residue in its catalytic domain inactivates its kinase function. Human HIPK4 harbors multiple putative serine/threonine- and tyrosine-specific phsophorylation sites and also contains four high probability sumoylation sites, findings that suggest its function to be modulated by post-translational modifications. HIPK4 has been so named in the database because of its sequence homology to HIPK1, 2 and 3 predominantly within its catalytic domain. However, HIPK4 is smaller in size than the known HIPKs and has additional distinct features suggesting it to be a unique member of the HIPK family. Further functional characterization of HIPK4 is needed and will prove valuable to ascertain whether it performs distinct functions or share overlapping functions with other HIPKs.