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ACS Chem Biol. 2017 Aug 18;12(8):2139-2148. doi: 10.1021/acschembio.6b01014. Epub 2017 Jul 10.

Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells.

Author information

1
Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
2
Chemical Biology Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
3
Department of Neurology, Harvard Medical School , Boston, Massachusetts 02115, United States.
4
Chemical Neurobiology Laboratory, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
5
Center for Systems Biology, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
6
Infectious Diseases Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
7
Schizophrenia and Bipolar Disorder Program, McLean Hospital , Belmont, Massachusetts 02478, United States.

Abstract

The AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and β-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1). Together, the PI3K-AKT signaling pathway plays pivotal roles in many cellular systems, including in the central nervous system where it governs both neurodevelopment and neuroplasticity. Recently, lysine residues (Lys14 and Lys20) on AKT, located within its pleckstrin homology (PH) domain that binds to membrane-bound PIP3, have been found to be acetylated under certain cellular contexts in various cancer cell lines. These acetylation modifications are removed by the enzymatic action of the class III lysine deacetylases, SIRT1 and SIRT2, of the sirtuin family. The extent to which reversible acetylation regulates AKT function in other cell types remains poorly understood. We report here that AKT kinase activity is modulated by a class IIb lysine deacetylase, histone deacetylase 6 (HDAC6), in human neural progenitor cells (NPCs). We find that HDAC6 and AKT physically interact with each other in the neuronal cells, and in the presence of selective HDAC6 inhibition, AKT is acetylated at Lys163 and Lys377 located in the kinase domain, two novel sites distinct from the acetylation sites in the PH-domain modulated by the sirtuins. Measurement of the functional effect of HDAC6 inhibition on AKT revealed decreased binding to PIP3, a correlated decrease in AKT kinase activity, decreased phosphorylation of Ser552 on β-catenin, and modulation of neuronal differentiation trajectories. Taken together, our studies implicate the deacetylase activity of HDAC6 as a novel regulator of AKT signaling and point to novel mechanisms for regulating AKT activity with small-molecule inhibitors of HDAC6 currently under clinical development.

PMID:
28628306
DOI:
10.1021/acschembio.6b01014
[Indexed for MEDLINE]

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