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

Nature Communications
Lintao SongSheng-Cai Lin

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 meta...Continue Reading

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Citations

Feb 9, 2021·Molecular & Cellular Oncology·Shu-Yong Lin, Sheng-Cai Lin
May 1, 2021·International Journal of Molecular Sciences·Laura BrohéeChristophe Deroanne

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Methods Mentioned

BETA
co-immunoprecipitation
pull-down
immunoprecipitation
acetylation
xenografts
xenograft
phosphotransferase-1
PCR
transfection
genotyping

Software Mentioned

JACoP
Analyst
Image J

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