MIG-15, a NIK ortholog of the STE20 family of serine/threonine protein kinases, is involved in cell migration and cell signaling in Caenorhabditis elegans

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 (Hedgecock et al., 1990; Devore et al., 1995; Sawa et al., 1996). 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 (Y. C. Su et al., 1997). 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 (Pombo et al., 1995). The regulatory domain of MIG-15/NIK contains a 40-residue motif that is shared by one other protein called citron, a presumptive RHO/RAC effector (Madaule et al., 1995). 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 localized to the adherens junctions during planar movement of hypodermal cells, and to the membrane sites where active signaling is likely occurring between the neighboring cells. These results suggest that MIG-15 may function to coordinate cell movement and cell-cell signaling.;On the basis of these findings, we propose that mig-15 is involved in multiple signaling pathways including the SAPK/JNK pathway and the Wingless pathway. Moreover, mig-15 may be a key regulator that integrate multiple signaling pathways and coordinate these with actin cytoskeleton rearrangement.