The Tumor Suppressor Kinase LKB1 Activates the Downstream Kinases SIK2 and SIK3 to Stimulate Nuclear Export of Class IIa Histone Deacetylases

Walkinshaw, Donald R.; Weist, Ryan; Kim, Go-Woon; You, Linya; Xiao, Lin; Nie, Jianyun; Li, Cathy S.; Zhao, Songping; Xu, Mengting; Yang, Xiang-Jiao

doi:10.1074/jbc.m113.456996

Cited by 85 publications

(79 citation statements)

References 82 publications

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“…Two possible mechanisms have been suggested: (i) cAMP activates PKA, phosphorylates MEF2D, and then stimulates MEF2D binding and nuclear localization of HDAC4; and (ii) cAMP indirectly activates PP2A, which in turn dephosphorylates HDAC4 and inhibits its 14-3-3 binding and cytoplasmic localization (45,46). We and others have recently demonstrated that LKB1 activates SIK2 and SIK3 to promote phosphorylation at 14-3-3 binding sites of class IIa HDACs and stimulate their cytoplasmic localization (47,48,89). As PKA phosphorylates LKB1 and SIKs (49 -51), a third possible mechanism is that cAMP acts through the LKB1-SIK kinase cascade to regulate nucleocytoplasmic trafficking of HDAC4.…”

Section: ;Hdac5mentioning

confidence: 99%

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*

Walkinshaw

Weist

Xiao

et al. 2013

Journal of Biological Chemistry

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Background: Nucleocytoplasmic trafficking of class IIa histone deacetylases is crucial for various biological processes. Results: cAMP induces dephosphorylation at an SP motif conserved in HDAC4, HDAC5, and HDAC9 but not in HDAC7. Conclusion: Dephosphorylation at the SP motif governs cAMP sensitivity and nuclear localization of class IIa histone deacetylases. Significance: Cellular signaling pathways may act upon cAMP to promote dephosphorylation and nuclear localization of class IIa histone deacetylases.

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Section: ;Hdac5mentioning

confidence: 99%

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*

Walkinshaw

Weist

Xiao

et al. 2013

Journal of Biological Chemistry

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“…Abbreviations: ALP, alkaline phosphatase; GFP, green fluorescent protein; OSKM, Oct4, Sox2, KLF4, and c-Myc; Ubc9, ubiquitin conjugating enzyme 9; WB, western blotting. Immunofluorescence Microscopy GFP and indirect immunofluorescence microscopic analyses were performed as previously described [26,27].…”

Section: Immunoblottingmentioning

confidence: 99%

The SUMO Conjugating Enzyme Ubc9 Is Required for Inducing and Maintaining Stem Cell Pluripotency

et al. 2014

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Sumoylation adds a small ubiquitin-like modifier (SUMO) polypeptide to the e-amino group of a lysine residue. Reminiscent of ubiquitination, sumoylation is catalyzed by an enzymatic cascade composed of E1, E2, and E3. For sumoylation, this cascade uses Ubc9 (ubiquitin conjugating enzyme 9, now officially named ubiquitin conjugating enzyme E2I [UBE2I]) as the sole E2 enzyme. Here, we report that expression of endogenous Ubc9 increases during reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. In addition, this E2 enzyme is required for reprogramming as its suppression dramatically inhibits iPS cell induction. While Ubc9 knockdown does not affect survival of MEFs and immortalized fibroblasts, Ubc9 is essential for embryonic stem cell (ESC) survival. In addition, we have found that Ubc9 knockdown stimulates apoptosis in ESCs but not in MEFs. Furthermore, the knockdown decreases the expression of the well-known pluripotency marker Nanog and the classical reprogramming factors Klf4, Oct4, and Sox2 in ESCs. Together, these observations indicate that while dispensable for fibroblast survival, the sole SUMO E2 enzyme Ubc9 plays a critical role in reprogramming fibroblasts to iPS cells and maintaining ESC pluripotency. STEM CELLS

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“…Class IIa HDACs are implicated in a wide array of biological processes, including the control of GLUT4 expression during adipogenesis and the activity of FOXO transcription factors Weems and Olson, 2011). Interestingly, they are suggested to be targets for AMPK or SIK phosphorylation in Drosophila, Caenorhabditis elegans and in mammals (Berdeaux et al, 2007;van der Linden et al, 2007;Walkinshaw et al, 2013;Wang et al, 2011). In Drosophila, the regulation of HDAC4 by a SIK isoform is important for lipid accumulation in response to feeding and starvation (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Henriksson

Säll

Gormand

et al. 2014

Journal of Cell Science

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Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation. Silencing of SIK2 resulted in reduced GLUT4 (also known as SLC2A4) protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased levels of GLUT4. Overexpression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2-CRTC2-HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that the cAMP-PKA pathway reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 increases GLUT4 levels and glucose uptake in adipocytes.

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The Tumor Suppressor Kinase LKB1 Activates the Downstream Kinases SIK2 and SIK3 to Stimulate Nuclear Export of Class IIa Histone Deacetylases

Cited by 85 publications

References 82 publications

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*

The SUMO Conjugating Enzyme Ubc9 Is Required for Inducing and Maintaining Stem Cell Pluripotency

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

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