Gupta Keshav, Kommineni Nagalakshmi, Bogadi Tanuja, Alamuru-Yellapragada Neeraja P, Maddika Subbareddy
Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Uppal, Hyderabad, Telangana, 500039, India.
Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
EMBO Rep. 2025 Sep 16. doi: 10.1038/s44319-025-00576-5.
mTOR (mechanistic target of rapamycin) kinase is a pivotal regulator of cellular growth and metabolism, integrating signals from nutrients and growth factors. It functions through the assembly of two distinct complexes, mTORC1 and mTORC2, which differ in their substrate specificity and regulation. While the regulation of mTORC1 is well-characterized, less is known about the modulators of mTORC2 signaling. In this study, we identify tyrosine phosphatase PTPN22 as an mTORC2-associated protein. We provide evidence that PTPN22 is essential for the activation of the mTORC2/AKT axis, independent of cell lineage. Loss of PTPN22 results in impaired AKT phosphorylation in response to both basal and growth factor signals. Mechanistically, PTPN22 functions as a scaffolding protein that promotes the mSIN-RICTOR interaction, thereby maintaining mTORC2 complex integrity. Notably, this adaptor function of PTPN22 is independent of its tyrosine phosphatase activity. Functionally, we demonstrate that PTPN22 is required for cell growth and survival in both cellular models and nude mouse xenografts. Together, these findings reveal a non-catalytic role for phosphatase PTPN22 in mTORC2 assembly and function.
雷帕霉素作用机制靶点（mTOR）激酶是细胞生长和代谢的关键调节因子，整合来自营养物质和生长因子的信号。它通过两种不同复合物mTORC1和mTORC2的组装发挥作用，这两种复合物在底物特异性和调节方面存在差异。虽然mTORC1的调节已得到充分表征，但对mTORC2信号传导的调节因子了解较少。在本研究中，我们鉴定酪氨酸磷酸酶PTPN22为一种与mTORC2相关的蛋白。我们提供的证据表明，PTPN22对于mTORC2/AKT轴的激活至关重要，且不依赖于细胞谱系。PTPN22的缺失导致在基础信号和生长因子信号作用下AKT磷酸化受损。从机制上讲，PTPN22作为一种支架蛋白，促进mSIN-RICTOR相互作用，从而维持mTORC2复合物的完整性。值得注意的是，PTPN22的这种衔接子功能独立于其酪氨酸磷酸酶活性。在功能上，我们证明PTPN22在细胞模型和裸鼠异种移植中对于细胞生长和存活都是必需的。总之，这些发现揭示了磷酸酶PTPN22在mTORC2组装和功能中的非催化作用。
