RYK binds WNT5A and VANGL2

RYK is an atypical receptor tyrosine kinase-like receptor that is required for craniofacial and skeletal development, axon guidance and neuronal differentiation. RYK has an extracellular WNT-binding WIF domain, a putative tetrabasic cleavage site, an intracellular PDZ domain and a cytosolic RTK-like catalytic site that is rendered inactive by a number of substitutions at conserved positions (reviewed in Fradkin et al, 2010; Keeble et al, 2006a). The WIF domain of RYK has been shown to interact with WNT1, 3, 3A and 5A (Keeble et al, 2006b; Liu et al, 2005; Macheda et al, 2012; Schmitt et al, 2006). RYK-deficient mice show disruptions to cochlear hair cell orientation suggesting a role for RYK in the planar cell polarity (PCP) pathway. Consistent with this, RYK binds to the PCP protein VANGL2 as assessed by co-immunoprecipitation from HEK293 cells. Formation of a RYK:VANGL2 complex appears to stabilize VANGL2 protein levels through an unknown mechanism (Macheda et al, 2012; Andre et al, 2012). RYK:VANGL may activate RHO A in response to WNT signaling (Macheda et al, 2012).

RYK是一种不典型的受体酪氨酸激酶样受体，对于颅面和骨骼发育、轴突导向以及神经元分化至关重要。RYK携带有细胞外WNT结合的WIF结构域、一个假定的四碱基切割位点、一个细胞内PDZ结构域以及一个由保守位置上的多个替换所失活的细胞质RTK样催化位点（参见Fradkin等，2010；Keeble等，2006a）。研究显示，RYK的WIF结构域能够与WNT1、3、3A和5A相互作用（Keeble等，2006b；Liu等，2005；Macheda等，2012；Schmitt等，2006）。RYK缺陷型小鼠的耳蜗毛细胞定向出现紊乱，这表明RYK在平面细胞极性（PCP）通路中扮演着一定角色。与此一致，RYK通过HEK293细胞的共免疫沉淀实验被证实与PCP蛋白VANGL2结合。RYK:VANGL2复合物的形成似乎通过一种未知的机制稳定了VANGL2蛋白的水平（Macheda等，2012；Andre等，2012）。RYK:VANGL可能在WNT信号传导的刺激下激活RHO A（Macheda等，2012）。