NIK IS A NEW STE20-RELATED KINASE THAT BINDS NCK AND MEKK1 AND ACTIVATES THE SAPK JNK CASCADE VIA A CONSERVED REGULATORY DOMAIN/

Nck, an adaptor protein composed of one SH2 and three SH3 domains, is a common target for a variety of cell surface receptors, We have ident ified a novel mammalian serine/threonine kinase that interacts with th e SH3 domains of Nck, termed Nck Interacting Kinase (NIK), This kinase is most homologous to the Sterile 20 (Ste20) family of protein kinase s. Of the members of this family, GCK and MSST1 are most similar to NI K in that they bind neither Cdc42 nor Rac and contain an N-terminal ki nase domain with a putative C-terminal regulatory domain, Transient ov erexpression of NIK specifically activates the stress-activated protei n kinase (SAPK) pathway, Both the kinase domain and C-terminal regulat ory region of NIK are required for full activation of SAPK, NIK likely functions upstream of MEKK1 to activate this pathway; a dominant-nega tive MEK kinase 1 (MEKK1) blocks activation of SAPK by NIK, MEKK1 and NIK also associate in cells and this interaction is mediated by regula tory domains on both proteins, Two other members of this kinase family , GCK and HPK1, contain C-terminal regulatory domains with homology to that of NIK, These findings indicate that the C-terminal domain of th ese proteins encodes a new protein domain family and suggests that thi s domain couples these kinases to the SAPK pathway, possibly by intera cting with MEKK1 or related kinases.