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，它在许多人类癌症中均被激活。mTOR存在于不同的复合物中，这些复合物要么由AKT调节（mTORC1），要么处于上游并对其进行调节（mTORC2）。对mTORC2活动的治理了解甚少。在这里，我们报告造血祖细胞中的跨膜分子与RICTOR（mTORC2的重要组成部分）发生物理相互作用并抑制其生长。mTORC2（UT2）的上游负调节mTORC2的酶活性，降低AKT ^S473，PKCα和NDRG1磷酸化并以mTORC2依赖性方式增加FOXO转录活性。在已知对mTORC2敏感的T细胞急性淋巴白血病（T-ALL）模型中，调节UT2水平可改变动物的存活率。这些研究确定了造血细胞中mTORC2上游的抑制成分，该成分可以降低NOTCH诱导的T-ALL的死亡率。mTORC2的跨膜抑制剂可能提供一个有吸引力的目标，以影响这一关键的细胞调节途径。