Phosphorylation of Serine 399 in LKB1 Protein Short Form by Protein Kinase Cζ Is Required for Its Nucleocytoplasmic Transport and Consequent AMP-activated Protein Kinase (AMPK) Activation

Zhu, Huaqing; Moriasi, Cate; Zhang, Miao; Zhao, Yu; Zou, Ming

doi:10.1074/jbc.m112.443580

Cited by 27 publications

(15 citation statements)

References 40 publications

(85 reference statements)

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“…Previously, we demonstrated that zinc-induced neuronal death shows apoptotic and necrotic aspects in cortical cultures [ 18 ], and many compounds are involved in zinc toxicity, including PKC, NADPH oxidase, nNOS, PARP-1, ERK, and Egr-1 [ 13 , 14 , 16 , 66 ]. Several reports showed that PKCζ may be an upstream kinase for LKB1 phosphorylation [ 51 , 67 ] we also observed that LKB1 phosphorylation by zinc could be mediated by PKC, and showed that LKB1 phosphorylation was almost completely attenuated by GF109203X, the specific chemical inhibitor of PKC, (Fig. 3e ).…”

Section: Discussionsupporting

confidence: 73%

AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures

et al. 2016

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BackgroundWe reported that zinc neurotoxicity, a key mechanism of ischemic neuronal death, was mediated by poly ADP-ribose polymerase (PARP) over-activation following NAD+/ATP depletion in cortical cultures. Because AMP-activated protein kinase (AMPK) can be activated by ATP depletion, and AMPK plays a key role in excitotoxicity and ischemic neuronal death, we examined whether AMPK could be involved in zinc neurotoxicity in mouse cortical neuronal cultures.ResultsCompound C, an AMPK inhibitor, significantly attenuated zinc-induced neuronal death. Activation of AMPK was detected beginning 2 h after a 10-min exposure of mouse cortical neurons to 300 μM zinc, although a significant change in AMP level was not detected until 4 h after zinc treatment. Thus, AMPK activation might not have been induced by an increase in intracellular AMP in zinc neurotoxicity. Furthermore, we observed that liver kinase B1 (LKB1) but not Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), was involved in AMPK activation. Although STO-609, a chemical inhibitor of CaMKKβ, significantly attenuated zinc neurotoxicity, zinc-induced AMPK activation was not affected, which suggested that CaMKKβ was not involved in AMPK activation. Knockdown of LKB1 by siRNA significantly reduced zinc neurotoxicity, as well as zinc-induced AMPK activation, which indicated a possible role for LKB1 as an upstream kinase for AMPK activation. In addition, mRNA and protein levels of Bim, a pro-apoptotic Bcl-2 family member, were noticeably increased by zinc in an AMPK-dependent manner. Finally, caspase-3 activation in zinc-induced neuronal death was mediated by LKB1 and AMPK activation.ConclusionsThe results suggested that AMPK mediated zinc-induced neuronal death via up-regulation of Bim and activation of caspase-3. Rapid activation of AMPK was detected after exposure of cortical neuronal cultures to zinc, which was induced by LKB1 activation but not increased intracellular AMP levels or CaMKKβ activation. Hence, blockade of AMPK in the brain may protect against zinc neurotoxicity, which is likely to occur after acute brain injury.

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Section: Discussionsupporting

confidence: 73%

AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures

et al. 2016

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“…We found that PSI did not influence phosphorylation of the target of AMPK ACC which would indicate that PKCζ acts downstream of AMPK. Phosphorylation of liver kinase B1 by PKCζ was shown to be necessary for metformin activation of AMPK in A549 distal airway cells . However, our data is supported by evidence from heart cells where metformin increased phosphorylation of PKCζ and that PKCζ activity did not influence metformin phosphorylation of AMPK …”

Section: Discussionsupporting

confidence: 72%

Metformin attenuates the effect of Staphylococcus aureus on airway tight junctions by increasing PKCζ‐mediated phosphorylation of occludin

Kalsi

Garnett

Patkee

et al. 2018

J Cellular Molecular Medi

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Airway epithelial tight junction (TJ) proteins form a resistive barrier to the external environment, however, during respiratory bacterial infection TJs become disrupted compromising barrier function. This promotes glucose flux/accumulation into the lumen which acts as a nutrient source for bacterial growth. Metformin used for the treatment of diabetes increases transepithelial resistance (TEER) and partially prevents the effect of bacteria but the mechanisms of action are unclear. We investigated the effect of metformin and Staphylococcus aureus on TJ proteins, zonula occludins (ZO)‐1 and occludin in human airway epithelial cells (H441). We also explored the role of AMP‐activated protein kinase (AMPK) and PKCζ in metformin‐induced effects. Pretreatment with metformin prevented the S. aureus‐induced changes in ZO‐1 and occludin. Metformin also promoted increased abundance of full length over smaller cleaved occludin proteins. The nonspecific PKC inhibitor staurosporine reduced TEER but did not prevent the effect of metformin indicating that the pathway may involve atypical PKC isoforms. Investigation of TJ reassembly after calcium depletion showed that metformin increased TEER more rapidly and promoted the abundance and localization of occludin at the TJ. These effects were inhibited by the AMPK inhibitor, compound C and the PKCζ pseudosubstrate inhibitor (PSI). Metformin increased phosphorylation of occludin and acetyl‐coA‐carboxylase but only the former was prevented by PSI. This study demonstrates that metformin improves TJ barrier function by promoting the abundance and assembly of full length occludin at the TJ and that this process involves phosphorylation of the protein via an AMPK‐PKCζ pathway.

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“…As a member of the atypical protein kinase C subfamily, PKCζ phosphorylates LKB1 at Ser-428/431 and mediates activation of AMPK in endothelial cells6061. We measured p-PKCζ levels (Thr410/403) and detected its elevation in LAR- but not PTPσ-overexpressing cells following CSPG stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Ohtake

Wong

Abdul-Muneer

et al. 2016

Sci Rep

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Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.

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Phosphorylation of Serine 399 in LKB1 Protein Short Form by Protein Kinase Cζ Is Required for Its Nucleocytoplasmic Transport and Consequent AMP-activated Protein Kinase (AMPK) Activation

Cited by 27 publications

References 40 publications

AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures

AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures

Metformin attenuates the effect of Staphylococcus aureus on airway tight junctions by increasing PKCζ‐mediated phosphorylation of occludin

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

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