The STE20 Kinase HGK Is Broadly Expressed in Human Tumor Cells and Can Modulate Cellular Transformation, Invasion, and Adhesion

Abstract

HGK (hepatocyte progenitor kinase-like/germinal center kinase-like kinase) is a member of the human STE20/mitogen-activated protein kinase kinase kinase kinase family of serine/threonine kinases and is the ortholog of mouse NIK (Nck-interacting kinase). We have cloned a novel splice variant of HGK from a human tumor line and have further identified a complex family of HGK splice variants. We showed HGK to be highly expressed in most tumor cell lines relative to normal tissue. An active role for this kinase in transformation was suggested by an inhibition of H-Ras V12 -induced focus formation by expression of inactive, dominantnegative mutants of HGK in both fibroblast and epithelial cell lines. Expression of an inactive mutant of HGK also inhibited the anchorage-independent growth of cells yet had no effect on proliferation in monolayer culture. Expression of HGK mutants modulated integrin receptor expression and had a striking effect on hepatocyte growth factor-stimulated epithelial cell invasion. Together, these results suggest an important role for HGK in cell transformation and invasiveness.The mammalian STE20/mitogen-activated protein kinase kinase kinase kinase (MAP4K) family consists of 28 serine/threonine kinases related in their catalytic domains (reviewed in reference 14). By analogy with the prototype STE20 kinase in Saccharomyces cerevisiae, mammalian MAP4K kinases are likely to regulate changes in transcription, cytoskeletal organization, and cell cycle progression in response to extracellular signals (17). Comparison of the overall domain structure places these kinases into two structural classes, the p21-activated protein kinases (PAKs) (1) and germinal center kinases (GCKs) (28). The GCK kinases lack the regulatory Cdc42/ Rac-interacting domain found in the PAKs, having instead an N-terminal kinase domain and a C-terminal extension of variable length. Unlike PAKs, several GCKs appear to be activated in the absence of stimuli when overexpressed (3,10,38), suggesting that these kinases are regulated either by oligomerization or by binding of negative regulatory factors.GCK kinases show little sequence homology outside of the kinase domain and are further broken down into nine subfamilies (14, 31a). HGK (hepatocyte progenitor kinase-like/GCKlike kinase) is one of four members of the GCK group IV (recently renamed the MSN subfamily) that also includes TNIK, MINK, and NRK/NESK (13,22,27,35,51). HGK, TNIK, and MINK are highly homologous in their kinase and C-terminal domains (about 92 and 87% amino acid identity, respectively), with variability in the intervening region that is less conserved (53% between HGK and TNIK). NRK/NESK is more divergent, with only 59% homology in the kinase domain and 37% homology in the C-terminal domain. The C-terminal domain is a citron homology (CNH) domain, named for citron rho-interacting kinase (CRIK), where it was first described (16,31). CNH domains are found not only in the GCK group IV/MSN kinases but also in group I GCKs (KHS subfamily) (14, 31a), as well as in pr...

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