Akt signalling is central to cell survival, metabolism, protein and lipid homeostasis, and is impaired in Parkinson's disease(PD). Akt activation is reduced in the PD brain, and by many PD-causing genes, including PINK1(PTEN-induced putative kinase-1). This study investigated the mechanisms by which PINK1 regulates Akt signalling. Our results reveal for the first time that PINK1 constitutively activates Akt in a PINK1-kinase dependent manner in the absence of growth factors, and enhances Akt activation in normal growth medium. In PINK1 modified MEFs, agonist-induced Akt signalling failed in the absence of PINK1, due to significantly impaired PINK1 kinase-dependent increases in PI(3,4,5)P3 at both plasma membrane and Golgi. In the absence of PINK1, PI(3,4,5)P3 levels did not increase in the Golgi, and there was significant Golgi fragmentation, a recognised characteristic of PD neuropathology. PINK1 kinase activity protected the Golgi from fragmentation in an Akt-dependent fashion. This study demonstrates a new role for PINK1 as a primary upstream activator of Akt via PINK1 kinase-dependent regulation of its primary activator PI(3,4,5)P3, providing novel mechanistic information on how loss of PINK1 impairs Akt signalling in PD.
The Parkinson's gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3
These authors contributed equally to this work
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Rachel M. Furlong, Andrew Lindsay, Karen E. Anderson, Phillip T. Hawkins, Aideen M. Sullivan, Cora O'Neill; The Parkinson's gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3. J Cell Sci 2019; jcs.233221. doi: https://doi.org/10.1242/jcs.233221
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