MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans

Abstract

The signalling protein Wnt regulates transcription factors containing high-mobility-group (HMG) domains to direct decisions on cell fate during animal development. In Caenorhabditis elegans, the HMG-domain-containing repressor POP-1 distinguishes the fates of anterior daughter cells from their posterior sisters throughout development, and Wnt signalling downregulates POP-1 activity in one posterior daughter cell called E. Here we show that the genes mom-4 and lit-1 are also required to downregulate POP-1, not only in E but also in other posterior daughter cells. Consistent with action in a common pathway, mom-4 and lit-1 exhibit similar mutant phenotypes and encode components of the mitogen-activated protein kinase (MAPK) pathway that are homologous to vertebrate transforming-growth-factor-beta-activated kinase (TAK1) and NEMO-like kinase (NLK), respectively. Furthermore, MOM-4 and TAK1 bind related proteins that promote their kinase activities. We conclude that a MAPK-related pathway cooperates with Wnt signal transduction to downregulate POP-1 activity. These functions are likely to be conserved in vertebrates, as TAK1 and NLK can downregulate HMG-domain-containing proteins related to POP-1.

When pathways collide: collaboration and connivance among signalling proteins in development

“…Early studies showed that overexpressed Wnt5a can block the stabilization of β-catenin induced by Wnt-1 39 . Expression of Wnt5a can also activate a nemo-like kinase (NLK) that phosphorylates TCF transcription factors, thus inhibiting canonical Wnt signaling 40,41 . In fact, it appears that simply inhibiting canonical signaling can, in some conditions, lead to PCP effects.…”

Wnt signaling through T-cell factor phosphorylation

“…In C. elegans, the phosphorylation of POP-1 is critical for POP-1 asymmetry and was proposed to promote signal-induced endodermal fate, although its physiological significance with respect to Mom-2/Wnt signaling remains to be fully established [48,51,52,[74][75][76]. In mammalian cells, Wnt1 can promote the phosphorylation of TCF4 [77], but there are conflicting reports regarding the ability of Wnt5a to stimulate LEF-1 and TCF-4 phosphorylation [77,78].…”

“…The two NLK phosphorylation sites on LEF-1 [78] correspond to a subset of the Wnt8-dependent, HIPK2 phosphorylation sites within TCF3, while two additional clusters of phosphorylation sites appear to be specific for HIPK2 [79]. Both NLK and HIPK2 cooperate in Wnt-1-dependent degradation of c-Myb in CV-1 fibroblasts [100], and both kinases can be stimulated by TGFβ-activated kinase (TAK1) [75,76,100,105,106]. Interestingly, HIPK2 has been shown to phosphorylate and activate NLK in vitro [100].…”

Wnt Signaling in Vertebrate Axis Specification

“…Nemolike kinase (Nlk) has been previously reported to phosphorylate TCF proteins (Ishitani et al 1999;Meneghini et al 1999) and is a positive regulator of Wnt8 signaling in anteroposterior patterning in zebrafish embryos (Thorpe and Moon 2004). In mammalian cells, Nlk and HIPK2 have been shown to regulate the stability of Myb oncoprotein in response to Wnt1 (KaneiIshii et al 2004), indicating that these kinases might also function together during axis specification.…”

“…In mammalian cells, Nlk and HIPK2 have been shown to regulate the stability of Myb oncoprotein in response to Wnt1 (KaneiIshii et al 2004), indicating that these kinases might also function together during axis specification. The pathway leading to TCF regulation in vertebrates is reminiscent of Wnt signaling in C. elegans, because LIT-1, a homolog of Nlk, and WRM-1, a b-catenin paralog, phosphorylates POP-1/TCF to enhance its nuclear export, leading to transcriptional derepression (Rocheleau et al 1997(Rocheleau et al , 1999Meneghini et al 1999;Lo et al 2004). Because POP-1 plays a dual role in gene target regulation, the reader is referred to other reviews foradditional information (Phillips and Kimble 2009;Sokol 2011).…”