MIG-15, a NIK Ortholog of the STE20 Family of Serine/Threonine Protein Kinases, is Involved in Cell Migration and Cell Signaling in C. elegans Xiaoping Zhu and Edward Hedgecock Biology Department, Johns Hopkins University, Baltimore MD 21218 The
mig-15 gene is required for a variety of cell movements and cell interactions in C. elegans. Mutations in
mig-15 disrupt embryonic and larval planar cell movements in the hypodermis, migration of the Q neuroblast descendants and outgrowth of the excretory canals. A number of signaling mechanisms including the Wingless pathway, the UNC-6/Netrin guidance cue and the receptor tyrosine kinase pathway have been implicated in these cellular processes.
mig-15 mutants share phenotypes with certain genes in all these signaling pathways.
mig-15 encodes an nematode ortholog of NIK, a newly isolated murine serine/theonine protein kinase of the STE20 family. Within the STE20 family, the MIG-15/NIK kinase domain is most homologous to GC kinases, which activate SAPK/JNK pathway in response to TNF-a and IL-1. These kinases may be regulated directly by RAB8 or other small G-proteins. The regulatory domain of MIG-15/NIK contains a 40-residue motif that is shared by citron, a presumptive RHO/RAC effector, and myotonic dystrophy kinase-related CDC42-binding kinase, which phosphorylates nonmuscle myosin light chain and activates actin-myosin contractility. NIK has been shown to associate with NCK, an adapter protein with one SH2 and three SH3 domains, suggesting MIG-15/NIK may form a protein complex with other signaling proteins including receptor tyrosine kinases. The hinge region of MIG-15/NIK contains two proline rich motifs proposed to be the recognition sites for SH3 domain binding. We have investigated the expression and localization pattern of MIG-15 protein using GFP tagging method. MIG-15::GFP is expressed in migrating Q cells and their descendants. MIG-15::GFP is localized to adherens junctions at the onset of Q cell migration and during planar movement of hypodermal cells. These results suggest that MIG-15 plays an important role in cell movement. A mammalian member of the STE20 family protein kinases, PAK, is directly regulated by CDC42 and RAC, small G-proteins involved in actin cytoskeleton dynamics, and is localized to focal adhesion complexes. PAK shares high homology with a myosin I heavy chain kinase. These results indicate a general role of STE20 family protein kinases in actin cytoskeleton dynamics. Taken together, we propose that
mig-15 plays an important role in pathways regulating actin cytoskeleton mediated by the RHO subgroup GTPases. Moreover,
mig-15 may function to coordinate actin cytoskeleton rearrangement with cell signaling.