Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Stem Cell Reports. 2014 Nov 11;3(5):832-40. doi: 10.1016/j.stemcr.2014.08.011. Epub 2014 Sep 25.
Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia (T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway.
丝氨酸/苏氨酸激酶 mTOR 是细胞增殖、存活和代谢反应的核心，在许多人类癌症中被激活。mTOR 存在于不同的复合物中，这些复合物要么被 AKT（mTORC1）调节，要么是其上游和调节因子（mTORC2）。mTORC2 活性的调控机制尚不清楚。在这里，我们在造血祖细胞中报告了一种跨膜分子，它与 mTORC2 的必需成分 RICTOR 相互作用并抑制其活性。mTORC2 的上游（UT2）负调控 mTORC2 的酶活性，以 mTORC2 依赖的方式降低 AKT(S473)、PKCα 和 NDRG1 的磷酸化，并增加 FOXO 的转录活性。调节 UT2 水平改变了已知对 mTORC2 敏感的 T 细胞急性淋巴细胞白血病（T-ALL）模型中的动物存活率。这些研究在造血细胞中鉴定了 mTORC2 的上游抑制性成分，可降低 NOTCH 诱导的 T-ALL 的死亡率。mTORC2 的跨膜抑制剂可能成为影响这一关键细胞调节途径的有吸引力的靶点。
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