Active calmodulin binds CAMK2

Calcium release in response to WNT5A has been shown to activate calcium/calmodulin-dependent protein kinase 2 (CAMK2) (Kuhl et al, 2000; Ishitani et al, 2003a). Human cells have 4 genes encoding CAMK: alpha, beta, delta and gamma. Alpha and beta isoforms are expressed in neuronal tissue while delta and gamma isoforms have broad tissue distribution. The enzyme exists as either a homo- or hetero- dodecamer of ill-defined stoichiometry. In the inactive state, the autoinhibitory loop of CAMK2 blocks the active site. Upon binding of Ca2+/calmodulin, the autoinhibitory loop is displaced, allowing subsequent autophosphorylation at T286 in CAMK2 alpha and activation of the kinase (reviewed in Stratton et al, 2013).

WNT-dependent activation of CAMK2 is inhibited by an interaction between oncogenic KRAS4B and calmodulin. This promotes tumorigenesis by relieving the suppression of beta-catenin dependent signaling mediated by the non-canonical WNT signaling pathway (Wang et al, 2015).

钙离子在WNT5A作用下的释放已被证实可激活钙/钙调蛋白依赖性蛋白激酶2（CAMK2）（Kuhl等，2000；Ishitani等，2003a）。人类细胞中含有4个编码CAMK的基因：α、β、δ和γ。α和β亚型在神经元组织中表达，而δ和γ亚型具有广泛的组织分布。该酶以不明确的化学计量比的同源或异源十二聚体形式存在。在非活性状态下，CAMK2的自动抑制环会阻断活性位点。当与Ca2+/钙调蛋白结合时，自动抑制环被移位，从而允许CAMK2 α在T286位点的后续自磷酸化，并激活激酶（Stratton等，2013年综述）。依赖于WNT的CAMK2激活被癌基因KRAS4B与钙调蛋白之间的相互作用所抑制。这通过缓解由非经典WNT信号通路介导的β-连环蛋白依赖性信号通路的抑制，从而促进肿瘤的发生（Wang等，2015年）。