Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction
Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction
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DOI：
10.1074/jbc.m111.283580
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发表时间：
2011-12-02
影响因子：
4.8
通讯作者：
Manser, Ed
中科院分区：
文献类型：
--
作者：
Lin, Pao-Chun;Chan, Perry M.;Manser, Ed
溃缩蛋白反应介导蛋白广泛表达于多个基因（CRMPs 1-5）中，在细胞分裂和信号蛋白3A（Sema 3A）信号传导过程中发挥重要作用。然而，他们的行动方式仍然不透明。在这里，我们进行了体内和体外试验，证明CRMPs是一类新的微管相关蛋白（MAP）。在CRMP 1或CRMP 2及其衍生物的实验中，只有C-末端区域（残基490-572）介导微管结合。CRMPs的体内微管结合被紫杉醇或埃博霉素B消除，这是非常罕见的。CRMP 2缺失的细胞表现出不稳定的后期星形微管和改变纺锤体的位置。在基于细胞的测定中，所有CRMPs都稳定了间期微管，防止nocodazole介导的解聚，其中CRMP 1最有效。值得注意的是，CRMP 1或CRMP 2的82个残基的C-末端区域，与其他微管结合基序无关，足以稳定微管。在细胞中，我们证明了糖原合成酶激酶-3 β（GSK 3 β）抑制增强了这种活性。因此，CRMPs是一类新的MAP，其通过独特的基序结合，但与其他如Tau一样，被GSK 3 β拮抗。这种调节与对Sema 3A（曲马新）途径至关重要的此类激酶一致。这些发现对癌症和神经退行性变有意义。
Collapsin response mediator proteins are ubiquitously expressed from multiple genes (CRMPs 1-5) and play important roles in dividing cells and during semaphorin 3A (Sema3A)signaling. Nonetheless, their mode of action remains opaque. Here we carried out in vivo and in vitro assays that demonstrate that CRMPs are a new class of microtubule-associated protein (MAP). In experiments with CRMP1 or CRMP2 and their derivatives, only the C-terminal region (residues 490-572) mediated microtubule binding. The in vivo microtubule association of CRMPs was abolished by taxol or epothilone B, which is highly unusual. CRMP2-depleted cells exhibited destabilized anaphase astral microtubules and altered spindle position. In a cell-based assay, all CRMPs stabilized interphase microtubules against nocodazole-mediated depolymerization, with CRMP1 being the most potent. Remarkably, a 82-residue C-terminal region of CRMP1 or CRMP2, unrelated to other microtubule binding motifs, is sufficient to stabilize microtubules. In cells, we demonstrate that glycogen synthase kinase-3 beta (GSK3 beta) inhibition potentiates this activity. Thus, CRMPs are a new class of MAP that binds through a unique motif, but in common with others such as Tau, is antagonized by GSK3 beta. This regulation is consistent with such kinases being critical for the Sema3A (collapsin) pathway. These findings have implications for cancer and neurodegeneration.