PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT signaling.
PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT signaling.
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DOI：
10.18632/oncotarget.3674
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发表时间：
2018-05-18
期刊：
影响因子：
--
通讯作者：
Halmos B
中科院分区：
文献类型：
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作者：
Wang X;Li G;Koul S;Ohki R;Maurer M;Borczuk A;Halmos B
Pleckstrin同源样结构域家族A成员2（PHLDA 2）位于11 p15的肿瘤抑制区域内，并且其表达在几种恶性肿瘤类型中被抑制。我们最近确定PHLDA 2作为一个强大的诱导，致癌EGFR/ErbB 2信号转导的新型下游靶点。在免疫组织化学研究中，我们发现PHLDA 2蛋白表达与人肺癌中AKT活化正相关，证实了我们的数据，即PHLDA 2在致癌活化后被诱导，并可能作为AKT通路活化的生物标志物。我们发现，PHLDA 2过表达抑制AKT磷酸化，而PHLDA 2表达减少增加AKT活性。我们进一步发现PHLDA 2与AKT的PH结构域竞争结合膜脂质，从而直接抑制AKT易位到细胞膜和随后的活化。事实上，PHLDA 2过表达抑制了锚定非依赖性细胞生长，并且PHLDA 2表达降低导致细胞增殖增加和对EGFR/ErbB 2驱动的癌症的靶向药物的敏感性降低，证明了这种相互作用的功能相关性。总之，我们的研究表明，PHLDA 2受到EGFR/ErbB 2信号转导的强烈调控，并通过抑制肺癌中AKT的激活来抑制细胞增殖。我们强调了PHLDA 2作为AKT通路激活的潜在生物标志物的新作用。
Pleckstrin homology-like domain family A member 2 (PHLDA2) is located within the tumor suppressor region of 11p15, and its expression is suppressed in several malignant tumor types. We recently identified PHLDA2 as a robustly induced, novel downstream target of oncogenic EGFR/ErbB2 signaling. In an immunohistochemical study, we find that PHLDA2 protein expression correlates positively with AKT activation in human lung cancers corroborating our data that PHLDA2 is induced upon oncogenic activation and might serve as a biomarker for AKT pathway activation. We show that PHLDA2 overexpression inhibits AKT phosphorylation while decreased PHLDA2 expression increases AKT activity. We further find that PHLDA2 competes with the PH domain of AKT for binding of membrane lipids, thereby directly inhibiting AKT translocation to the cellular membrane and subsequent activation. Indeed, PHLDA2 overexpression suppresses anchorage-independent cell growth and decreased PHLDA2 expression results in increased cell proliferation and reduced sensitivity to targeted agents of EGFR/ErbB2-driven cancers demonstrating functional relevance for this interaction. In summary, our studies demonstrate that PHLDA2 is strongly regulated by EGFR/ErbB2 signaling and inhibits cell proliferation via repressing AKT activation in lung cancers in a negative feedback loop. We highlight a novel action for PHLDA2 as a potential biomarker for AKT pathway activation.