WRM-1 Activates the LIT-1 Protein Kinase to Transduce Anterior/Posterior Polarity Signals in C. elegans

The lit-1 gene encodes a MAPK-like protein similar to the Drosophila Nemo protein kinase and the mouse Nemo-like kinase (NLK).

“The lit-1 gene encodes a mitogen-activated protein kinase (MAPK)-like protein similar to the Drosophila Nemo protein kinase and the mouse Nemo-like kinase (NLK).”

LIT-1 interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a LIT-1 kinase domain-dependent manner.

“LIT-1 interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a LIT-1 kinase domain-dependent manner, indicating that these pathways converge at WRM-1 (22).”

In C. elegans, WRM-1 down-regulates, rather than activates, POP-1.

“whereas in C. elegans, WRM-1 down-regulates, rather than activates, POP-1 (16, 21, 22, 30).”

Wnt signaling and the MAPK-related cascade both act to control polarity by regulating POP-1, and integration of the two signals occurs at the level of complex formation between WRM-1 and LIT-1.

“These results suggest that Wnt signaling and the MAPK-related cascade both act to control polarity by regulating POP-1 and that integration of two signals occurs at the level of complex formation between WRM-1 and LIT-1.”

The mom-4 gene encodes a MAPK kinase kinase-like protein related to the mammalian protein kinase TAK1.

“The mom-4 gene encodes a MAPK kinase kinase-like protein related to the mammalian protein kinase TAK1.”

Mutations in lit-1 or mom-4 cause a loss of polarity and POP-1 asymmetry.

“Mutations in lit-1 or mom-4 cause a loss of polarity and POP-1 asymmetry (16, 22, 27).”

A MAPK-related pathway acts in concert with Wnt signaling to establish anterior-posterior polarity in C. elegans.

“Thus, a MAPK-related pathway acts in concert with Wnt signaling to establish anterior-posterior polarity in C. elegans.”

WRM-1 activates LIT-1 protein kinase, leading to phosphorylation of WRM-1, LIT-1, and POP-1.

“WRM-1 activates the LIT-1 protein kinase, leading to phosphorylation of WRM-1, LIT-1, and POP-1.”

In C. elegans, WRM-1 (β-catenin) directly interacts with and activates LIT-1 (NLK).

“In C. elegans, WRM-1 (β-catenin) directly interacts with and activates LIT-1 (NLK).”

Active LIT-1 phosphorylates WRM-1 and POP-1 (LEF-1/TCF).

“Active LIT-1 then phosphorylates WRM-1 and POP-1 (LEF-1/TCF) (22).”

In C. elegans, WRM-1 and LIT-1 form a stable protein complex in vivo.

“In C. elegans, WRM-1 and LIT-1 appear to form a stable protein complex in vivo (22).”

WRM-1 weakly binds full-length POP-1.

“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”

WRM-1 does not bind to the POP-1 β-catenin-binding domain per se.

“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”

POP-1 plays a negative role in Wnt signaling.

“POP-1 plays a negative role in Wnt signaling and is inhibited by WRM-1 through LIT-1-mediated phosphorylation of POP-1 (22).”

The C. elegans LIT-1 protein interacts directly with WRM-1.

“The C. elegans LIT-1 protein interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a manner that requires the LIT-1 kinase domain (22).”

Activation of LIT-1 by WRM-1 leads to phosphorylation of POP-1 and apparent changes in its subcellular localization.

“This activation leads to the phosphorylation of POP-1 and apparent changes in its subcellular localization (22).”

WRM-1 and POP-1 have opposing functions rather than working as cofactors.

“Thus, WRM-1 and POP-1, rather than working as cofactors, have opposing functions.”

WRM-1 protein binds to and activates LIT-1.

“Rocheleau et al. (22) have demonstrated that the WRM-1 protein binds to and activates LIT-1.”

WRM-1 is only 19% identical to vertebrate β-catenin.

“Indeed, WRM-1, which is only 19% identical to vertebrate β-catenin, does not bind to the POP-1 β-catenin-binding domain per se but weakly binds full-length POP-1 (14, 19, 22).”

The LIT-1-WRM-1 complex can phosphorylate POP-1 in a manner that requires the LIT-1 kinase domain.

“The C. elegans LIT-1 protein interacts directly with WRM-1, and this complex can phosphorylate POP-1 in a manner that requires the LIT-1 kinase domain (22).”

POP-1 is inhibited by WRM-1 through LIT-1-mediated phosphorylation of POP-1.

“POP-1 plays a negative role in Wnt signaling and is inhibited by WRM-1 through LIT-1-mediated phosphorylation of POP-1 (22).”

Phosphorylation inhibits LEF-1/TCF signaling by inducing redistribution of POP-1 from the nucleus to the cytoplasm.

“and by inducing redistribution of POP-1 from the nucleus to the cytoplasm (22).”

In both C. elegans and mammalian cells, the Nemo-like kinases LIT-1 and NLK, respectively, phosphorylate LEF-1/TCF.

“Furthermore, in both C. elegans and mammalian cells, the Nemo-like kinases LIT-1 and NLK, respectively, phosphorylate LEF-1/TCF.”

NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways.

“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”