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

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 malignancy.

journal_name

Nat Commun

journal_title

Nature communications

authors

Song L,Liu Z,Hu HH,Yang Y,Li TY,Lin ZZ,Ye J,Chen J,Huang X,Liu DT,Zhou J,Shi Y,Zhao H,Xie C,Chen L,Song E,Lin SY,Lin SC

doi

10.1038/s41467-020-19694-w

subject

Has Abstract

pub_date

2020-11-17 00:00:00

pages

5842

issue

1

issn

2041-1723

pii

10.1038/s41467-020-19694-w

journal_volume

11

pub_type

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