WNT mediated activation of DVL

The three human Dishevelled (DVL) proteins play a central and overlapping role in the transduction of the WNT signaling cascade (Lee et al, 2008; reviewed in Gao and Chen 2010). DVL activity is regulated by phosphorylation, although the details are not completely worked out. DVL likely exists as a phosphoprotein even in the absence of WNT stimulation, and is further phosphorylated upon ligand binding. Casein kinase 1epsilon (CSNK1E), casein kinase 2 (CSNK2) and PAR1 have all been reported to phosphorylate DVL (Willert et al, 1997; Sun et al, 2001; Cong et al, 2004; Ossipova et al, 2005). Upon pathway activation, phosphorylated DVL translocates to the plasma membrane through an interaction between the DVL PDZ domain and the FZD KTxxxW motif (Wong et al, 2003; Umbhauer et al, 2000; Kikuchi et al, 2011). At the plasma membrane, DVL is believed to oligomerize through its DIX domain, providing a platform for AXIN recruitment; recruitment of AXIN is also facilitated by interaction with LRP (Schwarz-Romond et al, 2007; Mao et al, 2001). DVL interacts with phosphatidylinositol-4-kinase type II (PI4KII) and phophatidylinositol-4-phosphate 5-kinase type I (PIP5KI) to promote formation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the membrane, which is required for the clustering and phosphorylation of LRP6 and the recruitment of AXIN (Pan et al, 2008; Qin et al, 2009).

三种人类Dishevelled（DVL）蛋白在WNT信号级联传导中扮演着核心且重叠的角色（参见Lee等，2008年；Gao和Chen，2010年综述）。DVL活性受磷酸化调控，尽管其具体机制尚未完全阐明。即使在缺乏WNT刺激的情况下，DVL很可能以磷酸蛋白的形式存在，并在配体结合后进一步磷酸化。Casein激酶1epsilon（CSNK1E）、Casein激酶2（CSNK2）和PAR1均已被报道可磷酸化DVL（参见Willert等，1997年；Sun等，2001年；Cong等，2004年；Ossipova等，2005年）。在通路激活后，磷酸化的DVL通过DVL PDZ结构域与FZD KTxxxW基序之间的相互作用转移至质膜。在质膜上，DVL被认为通过其DIX结构域形成寡聚体，为AXIN的募集提供平台；AXIN的募集也得益于与LRP的相互作用（参见Schwarz-Romond等，2007年；Mao等，2001年）。DVL与磷脂酰肌醇-4激酶II型（PI4KII）和磷脂酰肌醇-4-磷酸5激酶I型（PIP5KI）相互作用，以促进质膜中磷脂酰肌醇4,5-二磷酸（PI(4,5)P2）的形成，这对于LRP6的簇集和磷酸化以及AXIN的募集是必需的（参见Pan等，2008年；Qin等，2009年）。