SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer.
SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer.
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DOI：
10.1016/j.molcel.2014.09.023
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发表时间：
2014-11-20
期刊：
影响因子：
16
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Gasser JA;Inuzuka H;Lau AW;Wei W;Beroukhim R;Toker A
PIK3CA是编码磷脂酰肌醇3-激酶(PI 3-K)催化亚单位的基因，在乳腺癌中发生频率较高。蛋白激酶Akt被认为是PIK3CA的主要效应因子，但PI3-K介导Akt非依赖性致癌信号的机制尚不清楚。我们发现血清和糖皮质激素调节的激酶3(SGK3)在乳腺癌中扩增，并以依赖于磷酸肌醇磷酸酶INPP4B的方式在PIK3CA下游被激活。INPP4B的表达可增强SGK3的活性，抑制Akt的磷酸化。在体内，PIK3CA和INPP4B下游的SGK3的激活是3D增殖、侵袭性迁移和肿瘤发生所必需的。我们进一步证明SGK3通过Fbw7降解转移抑制因子NDRG1。我们提出了一个模型，在该模型中，携带致癌PIK3CA的乳腺癌激活SGK3信号而抑制Akt，表明INPP4B和SGK3在这些肿瘤中都具有致癌功能。
Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI 3-K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI 3-K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activates SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors.