MARK3-mediated phosphorylation of ARHGEF2 couples microtubules to the actin cytoskeleton to establish cell polarity.
MARK3-mediated phosphorylation of ARHGEF2 couples microtubules to the actin cytoskeleton to establish cell polarity.
复制标题
ARHGEF2伴侣微管与肌动蛋白细胞骨架的微管介导的磷酸化，以建立细胞极性。
DOI：
10.1126/scisignal.aan3286
复制
发表时间：
2017-10-31
影响因子：
7.3
通讯作者：
Rottapel R
中科院分区：
文献类型：
--
作者：
Sandí MJ;Marshall CB;Balan M;Coyaud É;Zhou M;Monson DM;Ishiyama N;Chandrakumar AA;La Rose J;Couzens AL;Gingras AC;Raught B;Xu W;Ikura M;Morrison DK;Rottapel R
PAR-1-Mark通路通过微管相关蛋白的磷酸化来控制细胞的极性。Rho-RAC鸟嘌呤核苷酸交换因子2(ARHGEF2)激活ras同源家族成员A(RHOA)，锚定在微管网络上，并通过与动力蛋白轻链Tctex-1类型1(DYNLT1)结合而被隔离在抑制状态。我们在哺乳动物细胞中发现，肝激酶B1(LKB1)激活了微管亲和力调节激酶3(Mark3)，而微管亲和力调节激酶3又在调节位点(Ser151)使ARHGEF2磷酸化。这种修饰通过在ARHGEF2中创建14-3-3结合位点来破坏ARHGEF2与DYNLT1之间的相互作用，从而引发ARHGEF2从微管解离。蛋白磷酸酶2A(PP2A)使ARHGEF2Ser151去磷酸化，恢复抑制状态。ARHGEF2被Mark3磷酸化可诱导RHOA激活、应力纤维和局灶性黏附的形成，这是三维培养中有组织的细胞结构所必需的。我们已经确定了一个由Mark3控制的调控开关，它将微管和肌动蛋白细胞骨架偶联，通过ARHGEF2建立上皮细胞的极性。
The PAR-1-MARK pathway controls cell polarity through the phosphorylation of microtubule-associated proteins. The Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates the ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state by binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that the liver kinase B1 (LKB1) activated the microtubule affinity regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at a regulatory site (Ser151). This modification disrupted the interaction between ARHGEF2 and DYNLT1 by creating a 14-3-3 binding site in ARHGEF2, thus triggering dissociation of ARHGEF2 from microtubules. Protein phosphatase 2A (PP2A) dephosphorylated ARHGEF2 Ser151 to restore the inhibited state. ARHGEF2 phosphorylation by MARK3 induced RHOA activation and stress fiber and focal adhesion formation and was required for organized cellular architecture in three-dimensional culture. We have identified a regulatory switch controlled by MARK3 that couples the microtubule and actin cytoskeletons to establish epithelial cell polarity through ARHGEF2.
登录
查看更多内容
影响因子：
50.3
作者：
Cullis, Jane;Meiri, David;Rottapel, Robert
通讯作者：
Rottapel, Robert
影响因子：
5.8
作者：
Craig, R;Beavis, RC
通讯作者：
Beavis, RC
影响因子：
3.3
作者：
Bhandari D;Zhang J;Menon S;Lord C;Chen S;Helm JR;Thorsen K;Corbett KD;Hay JC;Ferro-Novick S
通讯作者：
Ferro-Novick S
影响因子：
3.3
作者：
Biernat, J;Wu, YZ;Mandelkow, EM
通讯作者：
Mandelkow, EM
影响因子：
11.8
作者：
Chuang, JZ;Yeh, TY;Sung, CH
通讯作者：
Sung, CH