Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer
Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer
复制标题
胃癌中 PDZK1 表达缺失通过 PTEN 磷酸化激活 PI3K/AKT 信号传导
DOI：
10.1016/j.canlet.2019.03.043
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
He，Junqi
中科院分区：
文献类型：
--
作者：
Zhao，Chunjuan;Tao，Tao;He，Junqi
PTEN的磷酸化在胃癌的发生、发展中起重要作用。然而，PTEN磷酸化调控的潜在机制仍然很难理解。在本研究中，PDZK 1被确定为一种新的结合蛋白的PTEN通过其羧基端和PDZK 1的PDZ结构域的协会。PDZK 1通过与PTEN的直接相互作用，抑制了S380/T382/T383位点的PTEN磷酸化，进一步增强了PTEN抑制PI 3 K/AKT活化的能力。PDZK 1通过抑制PTEN的磷酸化，抑制PI 3 K/AKT的活化，从而抑制胃癌细胞的增殖。PDZK 1在胃癌组织中的表达常下调，与胃癌的进展及预后相关。PDZK 1的下调与临床标本中的PTEN失活、AKT信号传导和细胞增殖激活相关。因此，胃癌标本中低水平的PDZK 1通过S380/T382/T383簇的PTEN磷酸化和PI 3 K/AKT信号传导的组成性激活导致胃癌细胞增殖增加，这导致胃癌患者预后不良。
Phosphorylation of PTEN plays an important role in carcinogenesis and progression of gastric cancer. However, the underlying mechanism of PTEN phosphorylation regulation remains largely elusive. In the present study, PDZK1 was identified as a novel binding protein of PTEN by association of PTEN through its carboxyl terminus and PDZ domains of PDZK1. By direct interaction with PTEN, PDZK1 inhibited the phosphorylation of PTEN at S380/T382/T383 cluster and further enhanced the capacity of PTEN to suppress PI3K/AKT activation. PDZK1 suppressed gastric cancer cell proliferation by diminishing PI3K/AKT activation via inhibition of PTEN phosphorylationin vitroandin vivo. The expression of PDZK1 was frequently downregulated in gastric cancer specimens and correlated with progression and poor prognosis of gastric cancer patients. Downregulation of PDZK1 was associated with PTEN inactivation, AKT signaling and cell proliferation activation in clinical specimens. Thus, low levels of PDZK1 in gastric cancer specimens lead to increase proliferation of gastric cancer cells via phosphorylation of PTEN at the S380/T382/T383 cluster and constitutively activation of PI3K/AKT signaling, which results in poor prognosis of gastric cancer patients.