黑色素瘤中PPM1D介导的去磷酸化修饰调控NRAS蛋白功能的机制研究

黑色素瘤是致死率最高的一种皮肤肿瘤，并且对于传统的放射治疗和化学治疗的非常不敏感。NRAS致癌性突变是黑色素瘤发生的重要驱动子，也是黑色素瘤治疗和改善预后的关键靶点。但是，由于NRAS的蛋白结构表面相对平滑，没有明显的药物可结合位点，近几十年来直接针对NRAS突变蛋白的药物开发并不成功。蛋白的翻译后修饰介导着蛋白功能的调控，因此，以翻译后蛋白修饰为靶向为NRAS突变黑色素瘤的治疗提供了新的思路。前期研究发现了NRAS蛋白在第158位苏氨酸的新磷酸化位点，而PPM1D可能参与介导这一磷酸化位点的去磷酸化修饰并调控NRAS的蛋白功能。本项目旨在前期工作的基础上阐明 PPM1D 介导 NRAS的去磷酸化和功能增强的关键作用和分子机制，预期确认 PPM1D-NRAS 轴作为 NRAS 突变黑色素瘤精准干预的新颖靶向目标，为恶性黑色素瘤的临床个性化治疗提供夯实的理论基础。

Melanoma is the deadliest type of skin cancer, and resistant to the traditional radiotherapy and chemotherapy. The oncogenic mutation of NRAS is a key driver in melanomagenesis, and a critical therapeutic target for melanoma treatment and prognosis improvement. However, because of the relatively smooth protein structure, there is no well-defined drug binding pockets on the NRAS protein surface. It has been unsuccessful for the development of direct NRAS inhibitors in the decades. It is widely established that the protein function is regulated by posttranslational modifications, especially phosphorylation. Therefore, it provides a new direction to target enzymes mediating NRAS protein modifications for NRAS mutant melanoma treatment. Our previous studies have identified a new phosphorylation site of NRAS at Threonine 158 (T158), and the T158 dephosphorylation is mediated by PPM1D for potential regulation of NRAS functions. The project aims to elucidate the key role of PPM1D-mediated NRAS dephosphorylation in regulation of NRAS signaling and the underlying molecular mechanism. It is expected to identify the PPM1D-NRAS axis as a new target for precision intervention of melanoma, and provide a solid theoretical foundation for personalized treatment of malignant melanoma.