Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

作者：Lintao Song, Zhihua Liu, Hui-Hui Hu, Ying Yang, Terytty Yang Li, Zhi‐Zhong Lin, Jing Ye, Jianing Chen, Xi Huang, Dong-Tai Liu, Jing Zhou, Yiran Shi, Hao Zhao, Changchuan Xie, Lanfen Chen, Erwei Song, Shu‐Yong Lin, Sheng‐Cai Lin, Sheng‐Cai Lin, Sheng‐Cai Lin · 发表于：Nature Communications · 年份：2020 · DOI：10.1038/s41467-020-19694-w · 被引用次数：123 · 研究领域：Lipid metabolism and biosynthesis、Cancer, Lipids, and Metabolism、Metabolism, Diabetes, and Cancer

Abstract Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT; Lpin1 −/− mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer mali...