The mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling pathways from yeast to mammals. MAPK cascades consist of three members, MAP kinase kinase kinase (MAPKKK), MAP kinase kinase (MAPKK) and MAPK. Each of them consists of multiple subfamilies. Specific combinations of these components play a role in multiple cell signaling processes. ZAK/MLTK/MRK is a member of MLK subfamily MAPKKK, which is characterized by a leucine zipper and a sterile alpha motif (SAM) in addition to a kinase domain. Although overexpression of ZAK activates several MAPK cascades and affects gene expression, cell cycle and actin stress fiber in mammalian cells, its function in the whole animals is not clear. We have taken a genetic approach to define the role of ZAK in C. elegans. A C. elegans ZAK homolog,
zak-1, encodes a 746a.a. protein containing a kinase domain, leucine zipper and SAM similar to mammalian ZAK.
zak-1 was expressed in pharynx, intestine and some other tissues. We isolated a
zak-1 deletion mutant lacking most of kinase domain, leucine zipper and SAM. The
zak-1 deletion mutant worms showed growth arrest at L1 larval stage due to a severe feeding defect. Similar phenotype was observed in a deletion mutant of the
pmk-2 gene encoding a
p38 MAPK homolog. Furthermore, we isolated a MKK3/6 homolog, SEK-2, as a PMK-2 interacting protein using yeast two-hybrid screening. These results suggest that ZAK-1 constitutes the MAPK cascade with SEK-2 and PMK-2 to regulate feeding in C. elegans.