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Cell Rep 2013 Sep 26;46:1224-34. doi: 10.1016/j.celrep.2013.08.008.
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RAB8B is required for activity and caveolar endocytosis of LRP6.

Demir K , Kirsch N , Beretta CA , Erdmann G , Ingelfinger D , Moro E , Argenton F , Carl M , Niehrs C , Boutros M .

Wnt/β-catenin signaling plays an important role in embryonic development and adult tissue homeostasis. When Wnt ligands bind to the receptor complex, LRP5/6 coreceptors are activated by phosphorylation and concomitantly endocytosed. In vertebrates, Wnt ligands induce caveolin-dependent endocytosis of LRP6 to relay signal downstream, whereas antagonists such as Dickkopf promote clathrin-dependent endocytosis, leading to inhibition. However, little is known about how LRP6 is directed to different internalization mechanisms, and how caveolin-dependent endocytosis is mediated. In an RNAi screen, we identified the Rab GTPase RAB8B as being required for Wnt/β-catenin signaling. RAB8B depletion reduces LRP6 activity, β-catenin accumulation, and induction of Wnt target genes, whereas RAB8B overexpression promotes LRP6 activity and internalization and rescues inhibition of caveolar endocytosis. In Xenopus laevis and Danio rerio, RAB8B morphants show lower Wnt activity during embryonic development. Our results implicate RAB8B as an essential evolutionary conserved component of Wnt/β-catenin signaling through regulation of LRP6 activity and endocytosis.

PubMed ID: 24035388
Article link: Cell Rep

Species referenced: Xenopus laevis
Genes referenced: axin2 cav1 cltc ctnnb1 dnm1 dvl1 flrt3 foxh1 gal.2 il6 lrp5 lrp6 mapk1 mos myc nectin1 pc.1 rab8a rab8b runx1t1 smad2 stat3.2 wnt3a
Morpholinos: rab8b MO1 rab8b MO2

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