Journal
JOURNAL OF CELL SCIENCE
Volume 132, Issue 16, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.231886
Keywords
K-Ras; Phosphatidylserine; Phosphatidylinositol 4-phosphate; Phosphatidylinositol 4-kinase; Golgi; Mitochondria
Categories
Funding
- National Cancer Institute [R00-CA188593]
- National Institutes of Health [R21NS100077, 1R01NS089815]
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Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of post-translational modifications, H-Ras and N-Ras traffic to the PM from the Golgi via the classical exocytic pathway, but the exact mechanism of K-Ras trafficking to the PM from the ER is not fully characterized. ATP5G1 (also known as ATP5MC1) is one of the three proteins that comprise subunit c of the F-0 complex of the mitochondrial ATP synthase. In this study, we show that overexpression of the mitochondrial targeting sequence of ATP5G1 perturbs glucose metabolism, inhibits oncogenic K-Ras signaling, and redistributes phosphatidylserine (PtdSer) to mitochondria and other endomembranes, resulting in K-Ras translocation to mitochondria. Also, it depletes phosphatidylinositol 4-phosphate (PI4P) at the Golgi. Glucose supplementation restores PtdSer and K-Ras PM localization and PI4P at the Golgi. We further show that inhibition of the Golgilocalized PI4-kinases (PI4Ks) translocates K-Ras, and PtdSer to mitochondria and endomembranes, respectively. We conclude that PI4P at the Golgi regulates the PM localization of PtdSer and K-Ras. This article has an associated First Person interview with the first author of the paper.
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