Akt2 Negatively Regulates Assembly of the POSH-MLK-JNK Signaling Complex

Figueroa, Claudia; Tarras, Samantha L.; Taylor, Jennifer; Vojtek, Anne B.

doi:10.1074/jbc.m307357200

Cited by 78 publications

(53 citation statements)

References 30 publications

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“…In addition to modulation of PJAC components by phosphorylation, it appears that Akt may also regulate PJAC by nonenzymatic mechanisms. As discussed earlier, Akt2 (but not Akt1) can directly bind to POSH, and Akt2 binding appears to block binding of MLK3, inhibiting the apoptotic pathway by preventing PJAC assembly (23). Finally, in another isoformspecific nonenzymatic mechanism, Akt1 (but not Akt2) can bind directly to JIP1, an interaction that has been reported to reduce JNK activation and apoptotic signaling (33).…”

Section: Discussionmentioning

confidence: 96%

“…Recently a direct binding interaction between POSH and Akt2 was described, in which binding of Akt2 to POSH prevents MLK3 binding and thereby inhibits PJAC assembly and apoptotic signaling by JNK. This binding interaction was found to be specific to Akt2; Akt1 showed no such binding to POSH (23). However, despite this isoform-specific interaction of Akt2 and POSH, activated Akt1 is fully able to protect cells from apoptosis induced by overexpression of POSH (1,2).…”

Section: Poshmentioning

confidence: 91%

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Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt

Lyons¹,

Thorburn

Ryan

et al. 2007

Journal of Biological Chemistry

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POSH (Plenty of SH3 domains) binds to activated Rac and promotes apoptosis by acting as a scaffold to assemble a signal transduction pathway leading from Rac to JNK activation. Overexpression of POSH induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase Akt. We report here that POSH is a direct substrate for phosphorylation by Akt in vivo and in vitro, and we identify a major site of Akt phosphorylation as serine 304 of POSH, which lies within the Rac-binding domain. We further show that phosphorylation of POSH results in a decreased ability to bind activated Rac, as does phosphomimetic S304D and S304E mutation of POSH. S304D mutant POSH also shows a strongly reduced ability to induce apoptosis. These findings identify a novel mechanism by which Akt promotes cell survival. POSH3 (Plenty of SH3 domains) is a recently discovered proapoptotic protein that appears to be widely expressed in multiple cell types, although at low levels. POSH was first identified as a binding partner of activated Rac and has been shown to act as a scaffolding protein in a kinase cascade signaling pathway that leads to apoptotic cell death (1, 2). In this pathway, Rac activates one of the mixed lineage kinases (MLKs, a group of MAPKKKs), which in turn phosphorylate and activate MKK4 and/or MKK7 (which are MAPKKs) which then phosphorylate and activate c-Jun N-terminal kinases (JNKs, one group of MAPKs) (2). Activated JNKs induce release of cytochrome c from mitochondria and trigger subsequent apoptosis. POSH directly binds Rac, MLK, and another scaffold protein, JIP (JNK-interacting protein), which in turn binds MKK4/7 and JNK, to facilitate this pathway. This multiprotein signaling assembly has been termed PJAC, for POSH-JIP apoptotic complex (3). The role of POSH as a scaffold for this signaling complex appears to be critical; in an apoptotic model involving withdrawal of nerve growth factor from cultures of neuronally differentiated PC12 cells or rat primary sympathetic neurons, apoptosis was dramatically reduced by pretreatment with POSH short interfering RNA or antisense oligonucleotides (4).The decision of a cell to undergo apoptosis is not undertaken lightly; apoptotic pathways are subject to regulation at many levels, and cells must integrate a variety of pro-apoptotic and anti-apoptotic signals. Regulation of the PJAC apoptotic pathway appears to follow this pattern, with multiple regulatory interactions. One form of regulation of PJAC may lie in the expression level of POSH protein within cells. POSH is maintained within healthy cells at very low levels, at least in part by POSH auto-ubiquitination and proteasomal degradation (5). Increasing the level of POSH protein by microinjection or ectopic expression induces apoptosis in a variety of cell types (1, 2, 4, 6 -9).Another potential regulator of the POSH-JIP apoptotic complex appears to be the pro-survival kinase Akt, also known as protein kinase B. Three closely related Akt genes exist (AKT1-3) that have b...

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Section: Discussionmentioning

confidence: 96%

Section: Poshmentioning

confidence: 91%

Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt

Lyons¹,

Thorburn

Ryan

et al. 2007

Journal of Biological Chemistry

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“…Although both isoforms phosphorylate Plenty of SH3 domains (POSH) which induces apoptotic cell death, only Akt2 interacts directly with POSH (24,25).…”

Section: Discussionmentioning

confidence: 99%

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

Fohlin¹,

Pérez-Tenorio²,

Fornander³

et al. 2013

European Journal of Cancer

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“…Frequently used medications include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (49). However, these therapies only delay the development of ESRD, and do not effectively prevent the development of DN (50)(51)(52). GSK-3β is a serine/threonine kinase, which is expressed in all eukaryotic cells.…”

Section: Discussionmentioning

confidence: 99%

GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes

Wan

Liu

et al. 2016

Molecular Medicine Reports

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Abstract. The mechanism underlying epithelial-tomesenchymal transition (EMT) caused by high glucose (HG) stimulation in diabetic nephropathy (DN) remains to be fully elucidated. The present study investigated the effects of HG on EMT and the activity of glycogen synthase kinase 3β (GSK-3β) in podocytes and the kidneys of db/db mice, and assessed the effects of (2'Z, 3'E)-6-bromoindirubin-3'-oxime (BIO), an inhibitor of GSK-3β, on EMT and glomerular injury. The resulting data showed that the activity of GSK-3β was upregulated by HG and downregulated by BIO in the podocytes and the renal cortex. The expression levels of epithelial markers, including nephrin, podocin and synaptopodin, were decreased by HG and increased by BIO, whereas the reverse were true for mesenchymal markers, including α-smooth muscle actin (α-SMA) and fibronectin. The expression levels of β-catenin and Snail, in contrast to current understanding of the Wnt signaling pathway, were increased by HG and decreased by BIO. In addition, expression of the vitamin D receptor (VDR) was decreased by HG and increased by BIO. In conclusion, the present study revealed that the mechanism by which BIO inhibited HG-mediated EMT in podocytes and the renal cortex was primarily due to the VDR. Treatment with BIO protected renal function by maintaining the integrity of the filtration membrane and decreasing UAE, but not by regulating blood glucose. Therefore, GSK-3β may be used as a sensitive biomarker of DN, and its inhibition by BIO may be effective in the treatment of DN.

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Akt2 Negatively Regulates Assembly of the POSH-MLK-JNK Signaling Complex

Cited by 78 publications

References 30 publications

Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt

Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes

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