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PINK1/BRPK inhibits apoptotic cell death and enahances cellular invasiveness through an activation of mTORC2 pathway

The PINK1/BRPK gene encodes a serine/threonine kinase with a mitochondrial localization signal. Mutations in the gene is causatively linked to an autosomal recessive form of Parkinson’s disease (PD). We showed that PINK1/BRPK was expressed at a higher level in cancer cell lines with higher metastatic potential. When overexpressed, PINK1/BRPK blocked apoptotic cell death of cancer cells induced by various agents, including oxidative stress. Overexpression of wild-type PINK1/BRPK induced phosphorylation of Akt, an important anti-apoptotic protein. PINK1/BRPK protein is mostly localized in the mitochondria, but the protein is also detected in the cytoplasm and co-precipitated with Akt. Application of an Akt inhibitor abrogated the anti-apoptotic effect of PINK1/BRPK. Blocking the EGF receptor-PI3 kinase pathway, an authentic upstream pathway for Akt activation, did not affect phosphorylation of Akt by PINK1/BRPK, indicating that PINK1/BRPK activates Akt through a mechanism independent from the receptor-PI3 kinase pathway.

Another known upstream effector for Akt is mTORC2. We therefore examined mTORC2 in SH-SY5Y cells with overexpression of PINK1. PINK1/BRPK was co-precipitated with components of mTORC2 but not with a component of mTORC1. Prolonged treatment with rapamycin that is known to inhibit mTORC2 cancelled the effect of PINK1/BRPK, while brief treatment with rapamycin that is specific to mTORC1 showed no effect. Furthermore, overexpression of PINK1/BRPK enhanced cellular invasiveness in vitro. These results indicate that mTORC2 is a critical molecule to mediate the anti-apoptotic and pro-metastatic activity of PINK1/BRPK.

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Correspondence to Nam-ho Huh.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Murata, H., Sakaguchi, M., Kataoka, K. et al. PINK1/BRPK inhibits apoptotic cell death and enahances cellular invasiveness through an activation of mTORC2 pathway. BMC Proc 4 (Suppl 2), O9 (2010). https://doi.org/10.1186/1753-6561-4-S2-O9

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  • DOI: https://doi.org/10.1186/1753-6561-4-S2-O9

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