Role of the Rap2/TNIK kinase pathway in regulation of LRP6 stability for Wnt signaling

Dong-Seok Park, Jeong-Han Seo, Mina Hong, Sun-Cheol Choi
Biochemical and Biophysical Research Communications 2013 June 28, 436 (2): 338-43
The Wnt/β-catenin signaling pathway plays critical roles in early embryonic development, stem cell biology and human diseases including cancers. Although Rap2, a member of Ras GTPase family, is essential for the Wnt/β-catenin pathway during the body axis specification in Xenopus embryo, the mechanism underlying its regulation of Wnt signaling remains poorly understood. Here, we show that Rap2 is implicated in control of the stability of Wnt receptor, low-density lipoprotein receptor-related protein 6 (LRP6). Knockdown of Rap2 resulted in the proteasome and/or lysosome-dependent degradation of LRP6 both in the presence and absence of Wnt ligand stimulation. In line with this, constitutively active LRP6 lacking its extracellular domain, which is constitutively phosphorylated and resides in intracellular vesicles, was also degraded in the Rap2-silenced cells. In addition, Rap2 and LRP6 associated physically with each other. Furthermore, we found that TRAF2/Nck-interacting kinase (TNIK), a member of the Ste20 protein family, acts as a downstream effector of Rap2 in control of LRP6 stabilization. Consistently, TNIK could rescue the inhibitory effects of Rap2 depletion on Wnt-dependent gene transcription, reporter activation and neural crest induction. Taken together, these results suggest that Rap2 acts via TNIK to regulate the stability of LRP6 receptor for Wnt/β-catenin signaling.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"