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.

中文翻译：

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PI3-激酶在调节蛋白质作为氨基酸来源的使用中的关键作用

通过巨胞饮作用和胞外蛋白的溶酶体分解代谢回收氨基酸，可以使Ras转化的细胞在氨基酸贫乏的环境中生长。但是，在研究未转化的成纤维细胞时，我们发现Ras GTPases对于生长因子刺激的巨胞饮作用和胞外蛋白的溶酶体分解代谢是必不可少的。相反，我们建立了磷脂酰肌醇3-激酶（PI3-激酶）信号转导在细胞增生中的关键作用，该信号由蛋白质大胞饮作用支持。在PI3激酶的下游，不同的效应子在调节细胞外蛋白的摄取和分解代谢中具有相反的作用。营养性使用细胞外蛋白需要Rac1和PLC。相反，当游离氨基酸丰富时，Akt抑制摄入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缺失的细胞可以使用多种氨基酸来源生长。因此，PI3-激酶和PTEN突变在癌症中的流行可能部分是由于它们允许细胞应对不断变化的营养物利用率。