It is suggested that
mig-15, a nematode ortholog of Nck-interacting kinase (NIK) and a MAP kinase kinase kinase kinase (MAP4k) in Drosophila, may be a key regulator that integrates multiple signaling pathways and coordinates these with actin cytoskeleton rearrangement.We have previously found that the small GTPase
ced-10 rac and the rac-related gene
mig-2 are redundantly required for vulval cell migrations. We also found
mig-15 (loss of function, lf) mutants have defects in vulval cell migration. We therefore investigate the relationship between
mig-15 and racs during vulval development and the potentially downstream targets of
mig-15. We found that overexpression of
mig-15 caused defects in vulval cell migration. Also a
ced-10 mutation greatly enhanced the
mig-15 (lf) vulval defects but did not intefere with the
mig-15 overexpression phenotype. Overexpression of
mig-15 can partly rescue
ced-10;
mig-2 vulval defects, but overexpression of
ced-10 can not rescue the
mig-15 (lf) vulval defects. Collectively, these data strongly suggest that
mig-15 acts downstream of the racs. We also found that
ced-12, a mammalian ELMO and an upstream activator of
ced-10, greatly enhanced the
mig-15 (lf) defects, and
ced-12 mutations did not interfere with
mig-15 overexpression phenotype, suggesting that
mig-15 acts downstream of
ced-12. A mutation in
ina-1, an integrin receptor, enhanced the
mig-15 (lf) vulval defects, suggesting signaling through the integrin receptor may contribute to the vulval cell migration. Interestingly, c-Jun amino-terminal kinase(JNK)-1 and
p38 MAPK levels are reduced in
mig-15 (lf) mutant worms as measured by Western blot analysis, and
jnk-1 RNAi greatly enhanced
mig-15 (lf) defects, suggesting for the first time, that JNK is a mediator of
mig-15 pathway in worms.