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Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria.


ABSTRACT: 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 Golgi-localized 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.

SUBMITTER: Miller TE 

PROVIDER: S-EPMC6737909 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria.

Miller Taylor E TE   Henkels Karen M KM   Huddleston Mary M   Salisbury Richard R   Hussain Saber M SM   Sasaki Atsuo T AT   Cho Kwang-Jin KJ  

Journal of cell science 20190822 16


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 <i>F</i><sub>0</sub> complex of the m  ...[more]

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