Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mitigate these beneficial effects by promoting a negative feedback-loop comprising extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated kinase kinase 1/2 (MEK1/2)-dependent inactivation of PPARγ. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARγ. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARγ. Synthetic peptides were designed resembling the regulatory coiled-coil (CC) domain of MTMR7, and their activities studied in human cancer cell lines and C57BL6/J mice. MTMR7 formed a complex with PPARγ and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. MTMR7-CC peptides mimicked PPARγ-activation in vitro and in vivo due to LXXLL motifs in the CC domain. Molecular dynamics simulations and docking predicted that peptides interact with the steroid receptor coactivator 1 (SRC1)-binding site of PPARγ. Thus, MTMR7 is a positive regulator of PPARγ, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARγ.

过氧化物酶体增殖物激活受体-γ (PPARγ) 是一种转录因子，可被批准用于治疗 2 型糖尿病的激动剂药物化，但也抑制体内的致癌作用和细胞增殖。克尔斯滕大鼠肉瘤病毒癌基因同源物 ( KRAS)基因的激活突变通过促进包含细胞外信号调节激酶 1/2 (ERK1/2) 和丝裂原活化激酶激酶 1/2 (MEK1) 的负反馈环来减轻这些有益作用/2) PPARγ的依赖性失活。为了克服这种抑制机制，我们寻找新的 PPARγ 翻译后调节因子。磷酸肌醇磷酸酶Myotubularin-Related-Protein-7(MTMR7) 被鉴定为 PPARγ 的胞质相互作用伴侣。合成肽的设计类似于 MTMR7 的调节卷曲螺旋 (CC) 结构域，并在人类癌细胞系和 C57BL6/J 小鼠中研究了它们的活性。MTMR7 与 PPARγ 形成复合物，并通过抑制 ERK1/2 依赖性 PPARγ 磷酸化增加其转录活性。由于 CC 结构域中的 LXXLL 基序，MTMR7-CC 肽在体外和体内模拟了 PPARγ 激活。分子动力学模拟和对接预测肽与 PPARγ 的类固醇受体共激活因子 1 (SRC1) 结合位点相互作用。因此，MTMR7 是 PPARγ 的正调节剂，其通过合成肽的模拟克服了在癌细胞中活跃的抑制机制，这可能导致针对 PPARγ 的临床研究失败。