TGF and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells
TGF and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells
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DOI：
10.1074/jbc.ra117.001299
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发表时间：
2018-05-25
影响因子：
4.8
通讯作者：
Wang, Jing
中科院分区：
文献类型：
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作者：
Leiphrakpam, Premila D.;Brattain, Michael G.;Wang, Jing
异常细胞存活在癌症进展和转移中起着至关重要的作用。我们之前已经证明，ezrin（一种 cAMP 依赖性蛋白激酶 A 锚定蛋白 (AKAP)）在结直肠癌 (CRC) 肝转移中表达上调。埃兹蛋白 Thr-567 处的磷酸化可激活埃兹蛋白，并在与 XIAP 和存活蛋白上调相关的 CRC 细胞存活中发挥重要作用。在这项研究中，我们证明在 FET 和 GEO 结肠癌细胞中，敲低 ezrin 表达或抑制 Thr-567 的 ezrin 磷酸化可通过蛋白激酶 A (PKA) 以不依赖于 cAMP 的方式激活来增加细胞凋亡。转化生长因子 (TGF) 信号传导以 Smad3 依赖性和 Smad2 独立性方式抑制 ezrin 磷酸化，并通过 ezrin 介导的 PKA 激活调节促凋亡功能。另一方面，胰岛素样生长因子 1 受体 (IGF1R) 信号传导导致埃兹蛋白 Thr-567 磷酸化，导致 cAMP 依赖性 PKA 激活并增强细胞存活。进一步的研究表明，磷酸化的埃兹蛋白与 PKA RII 形成复合物，去磷酸化的埃兹蛋白从该复合物中解离，并促进 PKA RII 与 AKAP149 的结合，这两者都激活 PKA 并导致细胞存活或凋亡。因此，我们的研究揭示了TGF和IGF1R信号通过调节CRC中的ezrin磷酸化介导的差异PKA激活的新机制，从而导致不同的细胞命运。这是很重要的，因为TGF和IGF1R信号通路分别是充分表征的肿瘤抑制通路和致癌通路，在结直肠癌肿瘤发生和转移中发挥重要作用。我们的研究表明，它们通过调节埃兹蛋白的激活来相互影响并拮抗彼此的功能。因此，ezrin可能是结直肠癌的潜在治疗靶点。
Aberrant cell survival plays a critical role in cancer progression and metastasis. We have previously shown that ezrin, a cAMP-dependent protein kinase A-anchoring protein (AKAP), is up-regulated in colorectal cancer (CRC) liver metastasis. Phosphorylation of ezrin at Thr-567 activates ezrin and plays an important role in CRC cell survival associated with XIAP and survivin up-regulation. In this study, we demonstrate that in FET and GEO colon cancer cells, knockdown of ezrin expression or inhibition of ezrin phosphorylation at Thr-567 increases apoptosis through protein kinase A (PKA) activation in a cAMP-independent manner. Transforming growth factor (TGF) signaling inhibits ezrin phosphorylation in a Smad3-dependent and Smad2-independent manner and regulates pro-apoptotic function through ezrin-mediated PKA activation. On the other hand, ezrin phosphorylation at Thr-567 by insulin-like growth factor 1 receptor (IGF1R) signaling leads to cAMP-dependent PKA activation and enhances cell survival. Further studies indicate that phosphorylated ezrin forms a complex with PKA RII, and dephosphorylated ezrin dissociates from the complex and facilitates the association of PKA RII with AKAP149, both of which activate PKA yet lead to either cell survival or apoptosis. Thus, our studies reveal a novel mechanism of differential PKA activation mediated by TGF and IGF1R signaling through regulation of ezrin phosphorylation in CRC, resulting in different cell fates. This is of significance because TGF and IGF1R signaling pathways are well-characterized tumor suppressor and oncogenic pathways, respectively, with important roles in CRC tumorigenesis and metastasis. Our studies indicate that they cross-talk and antagonize each other's function through regulation of ezrin activation. Therefore, ezrin may be a potential therapeutic target in CRC.