PI3K/AKT pathway activation is thought to be a driving force in metastatic melanomas. Members of the pleckstrin homology (PH) domain leucine-rich repeat protein Ser/Thr specific phosphatase family (PHLPP1 and PHLPP2) can regulate AKT activation. By dephosphorylating specific serine residues in the hydrophobic motif, PHLPP1 and PHLPP2 restrain AKT signalings, thereby regulating cell proliferation and survival. We here show that PHLPP1 expression was significantly downregulated or lost and correlated with metastatic potential in melanoma. Forcing expression of either PHLPP1 or PHLPP2 in melanoma cells inhibited cell proliferation, migration, and colony formation in soft agar; but PHLPP1 had the most profound inhibitory effect on metastasis. Moreover, expression of PH mutant forms of PHLPP1 continued to inhibit metastasis, whereas a phosphatase-dead C-terminal mutant did not. The introduction of activated PHLPP1-specific targets AKT2 or AKT3 also promoted melanoma metastasis, while the non-PHLPP1 target AKT1 did not. AKT2 and AKT3 could even rescue the PHLPP1-mediated inhibition of metastasis. An AKT inhibitor blocked the activity of AKT2 and inhibited AKT2-mediated tumor growth and metastasis in a preclinical mouse model. Our data demonstrate that PHLPP1 functions as a metastasis suppressor through its phosphatase activity, and suggest that PHLPP1 represents a novel diagnostic and therapeutic marker for metastatic melanoma.

中文翻译：

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PHLPP1通过抑制AKT2激活介导黑色素瘤转移抑制。

PI3K / AKT途径的激活被认为是转移性黑色素瘤的驱动力。pleckstrin同源（PH）域中富含亮氨酸的重复蛋白Ser / Thr特异性磷酸酶家族（PHLPP1和PHLPP2）的成员可以调节AKT激活。通过使疏水基序中的特定丝氨酸残基去磷酸化，PHLPP1和PHLPP2抑制AKT信号传导，从而调节细胞增殖和存活。我们在这里显示，PHLPP1表达明显下调或丢失，并与黑色素瘤的转移潜能相关。迫使PHLPP1或PHLPP2在黑色素瘤细胞中表达抑制了软琼脂中的细胞增殖，迁移和集落形成；但PHLPP1对转移的抑制作用最深。此外，PH突变体PHLPP1的表达继续抑制转移，而磷酸酶死亡的C末端突变体则没有。激活的PHLPP1特异性靶标AKT2或AKT3的引入也促进了黑色素瘤转移，而非PHLPP1靶标AKT1则没有。AKT2和AKT3甚至可以挽救PHLPP1介导的转移抑制作用。在临床前小鼠模型中，AKT抑制剂可阻断AKT2的活性并抑制AKT2介导的肿瘤生长和转移。我们的数据表明，PHLPP1通过其磷酸酶活性充当转移抑制因子，并暗示PHLPP1代表了转移性黑素瘤的新型诊断和治疗标记。AKT2和AKT3甚至可以挽救PHLPP1介导的转移抑制作用。在临床前小鼠模型中，AKT抑制剂可阻断AKT2的活性并抑制AKT2介导的肿瘤生长和转移。我们的数据表明，PHLPP1通过其磷酸酶活性充当转移抑制因子，并暗示PHLPP1代表了转移性黑素瘤的新型诊断和治疗标记。AKT2和AKT3甚至可以挽救PHLPP1介导的转移抑制作用。在临床前小鼠模型中，AKT抑制剂可阻断AKT2的活性并抑制AKT2介导的肿瘤生长和转移。我们的数据表明，PHLPP1通过其磷酸酶活性充当转移抑制因子，并暗示PHLPP1代表了转移性黑素瘤的新型诊断和治疗标记。