Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8628-E8636. doi: 10.1073/pnas.1712726114. Epub 2017 Sep 25.
Ras-transformed cells can grow in amino acid-poor environments by recovering amino acids through macropinocytosis and lysosomal catabolism of extracellular proteins. However, when studying nontransformed fibroblasts, we found that Ras GTPases are dispensable for growth-factor-stimulated macropinocytosis and lysosomal catabolism of extracellular proteins. Instead, we establish a critical role for phosphatidylinositol 3-kinase (PI3-kinase) signaling in cell proliferation that is supported by protein macropinocytosis. Downstream of PI3-kinase, distinct effectors have opposing roles in regulating uptake and catabolism of extracellular proteins. Rac1 and PLC are required for nutritional use of extracellular proteins. In contrast, Akt suppresses lysosomal catabolism of ingested proteins when free amino acids are abundant. The interplay between these pathways allows cells with oncogenic PIK3CA mutations or PTEN deletion to grow using diverse amino acid sources. Thus, the prevalence of PI3-kinase and PTEN mutations in cancer may result in part because they allow cells to cope with fluctuating nutrient availability.
Ras 转化的细胞可以在氨基酸缺乏的环境中生长，通过巨胞饮作用和细胞外蛋白质的溶酶体分解来回收氨基酸。然而，在研究非转化成纤维细胞时，我们发现 Ras GTPases 对于生长因子刺激的巨胞饮作用和细胞外蛋白质的溶酶体分解不是必需的。相反，我们确立了磷脂酰肌醇 3-激酶（PI3-kinase）信号在细胞增殖中的关键作用，该作用得到了蛋白质巨胞饮作用的支持。在 PI3-kinase 的下游，不同的效应物在调节细胞外蛋白质的摄取和分解代谢方面发挥着相反的作用。Rac1 和 PLC 对于细胞外蛋白质的营养利用是必需的。相比之下，当游离氨基酸丰富时，Akt 会抑制吞噬的蛋白质的溶酶体分解代谢。这些途径之间的相互作用使具有致癌性 PIK3CA 突变或 PTEN 缺失的细胞能够利用多种氨基酸来源生长。因此，PI3-kinase 和 PTEN 突变在癌症中的普遍存在可能部分是由于它们使细胞能够应对不断变化的营养供应。
