PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling
PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling
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DOI：
10.1038/sj.emboj.7600979
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发表时间：
2006-02-22
期刊：
影响因子：
11.4
通讯作者：
Georgescu, MM
中科院分区：
文献类型：
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作者：
Takahashi, Y;Morales, FC;Georgescu, MM
PTEN是一种在许多人类癌症中经常失活的肿瘤抑制因子，其通过使磷酸肌醇脱磷酸化而直接拮抗磷脂酰肌醇-3- OH激酶（PI 3 K）的活性。我们在这里表明，PTEN直接与NHERF 1和NHERF 2（Na（+）/ H（+）交换调节因子）同源衔接蛋白通过PDZ基序的PTEN和PDZ 1结构域的NHERF 1或两个PDZ结构域的NHERF 2。NHERF被证明与血小板衍生生长因子受体（PDGFR）直接相互作用，并且我们证明了PTEN、NHERF和PDGFR之间三元复合物的组装。与野生型细胞相比，在NHERF 1（-/ -）小鼠胚胎成纤维细胞中，PDGFR刺激后PI 3 K途径的激活延长，这与在NHERF 1不存在时PTEN向PDGFR的募集缺陷一致.通过小干扰RNA消耗NHERF 2类似地增加PI 3 K信号传导。从表型上看，NHERF 1的缺失增强了PDGF诱导的细胞骨架重排和细胞的趋化性迁移。这些数据表明，在正常细胞中，NHERF蛋白将PTEN募集至PDGFR以限制PI 3 K的活化。
PTEN, a tumor suppressor frequently inactivated in many human cancers, directly antagonizes the activity of phosphatidylinositol-3- OH kinase ( PI3K) by dephosphorylating phosphoinositides. We show here that PTEN interacts directly with the NHERF1 and NHERF2 ( Na (+)/ H (+) exchanger regulatory factor) homologous adaptor proteins through the PDZ motif of PTEN and the PDZ1 domain of NHERF1 or both PDZ domains of NHERF2. NHERFs were shown to interact directly with platelet- derived growth factor receptor ( PDGFR), and we demonstrate the assembly of a ternary complex between PTEN, NHERFs and PDGFR. The activation of the PI3K pathway after PDGFR stimulation was prolonged in NHERF1( -/ -) mouse embryonic fibroblasts as compared to wild- type cells, consistent with defective PTEN recruitment to PDGFR in the absence of NHERF1. Depletion of NHERF2 by small interfering RNA similarly increased PI3K signaling. Phenotypically, the loss of NHERF1 enhanced the PDGF-induced cytoskeletal rearrangements and chemotactic migration of the cells. These data indicate that, in normal cells, NHERF proteins recruit PTEN to PDGFR to restrict the activation of the PI3K.