Jones Kevin T, Greer Elisabeth R, Pearce David, Ashrafi Kaveh
Department of Physiology and Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
PLoS Biol. 2009 Mar 3;7(3):e60. doi: 10.1371/journal.pbio.1000060.
The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of cancer, metabolic disease, and aging. The TOR kinase is found in two biochemically and functionally distinct complexes, termed TORC1 and TORC2. Aided by the compound rapamycin, which specifically inhibits TORC1, the role of TORC1 in regulating translation and cellular growth has been extensively studied. The physiological roles of TORC2 have remained largely elusive due to the lack of pharmacological inhibitors and its genetic lethality in mammals. Among potential targets of TORC2, the pro-survival kinase AKT has garnered much attention. Within the context of intact animals, however, the physiological consequences of phosphorylation of AKT by TORC2 remain poorly understood. Here we describe viable loss-of-function mutants in the Caenorhabditis elegans homolog of the TORC2-specific component, Rictor (CeRictor). These mutants display a mild developmental delay and decreased body size, but have increased lipid storage. These functions of CeRictor are not mediated through the regulation of AKT kinases or their major downstream target, the insulin-regulated FOXO transcription factor DAF-16. We found that loss of sgk-1, a homolog of the serum- and glucocorticoid-induced kinase, mimics the developmental, growth, and metabolic phenotypes of CeRictor mutants, while a novel, gain-of-function mutation in sgk-1 suppresses these phenotypes, indicating that SGK-1 is a mediator of CeRictor activity. These findings identify new physiological roles for TORC2, mediated by SGK, in regulation of C. elegans lipid accumulation and growth, and they challenge the notion that AKT is the primary effector of TORC2 function.
雷帕霉素靶蛋白（TOR）激酶协同调节基本的代谢和细胞过程，以支持生长、增殖、存活和分化，因此它被提议作为治疗癌症、代谢疾病和衰老的治疗靶点。TOR激酶存在于两种生化和功能不同的复合物中，称为TORC1和TORC2。在特异性抑制TORC1的化合物雷帕霉素的帮助下，TORC1在调节翻译和细胞生长中的作用已得到广泛研究。由于缺乏药理学抑制剂及其在哺乳动物中的遗传致死性，TORC2的生理作用在很大程度上仍然难以捉摸。在TORC2的潜在靶标中，促存活激酶AKT备受关注。然而，在完整动物的背景下，TORC2磷酸化AKT的生理后果仍知之甚少。在这里，我们描述了TORC2特异性组分Rictor（CeRictor）的秀丽隐杆线虫同源物中的可行功能丧失突变体。这些突变体表现出轻度的发育延迟和体型减小，但脂质储存增加。CeRictor的这些功能不是通过调节AKT激酶或其主要下游靶标——胰岛素调节的FOXO转录因子DAF-16介导的。我们发现，血清和糖皮质激素诱导激酶的同源物sgk-1的缺失模拟了CeRictor突变体的发育、生长和代谢表型，而sgk-1中的一个新的功能获得性突变则抑制了这些表型，表明SGK-1是CeRictor活性的介导者。这些发现确定了由SGK介导的TORC2在调节秀丽隐杆线虫脂质积累和生长中的新生理作用，并挑战了AKT是TORC2功能的主要效应器这一观点。
