Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization

An, Rong; Xavier, Gabriela da Silva; Semplici, Francesca; Vakhshouri, Saharnaz; Hao, Huai Xiang; Rutter, Jared; Pagano, Mario A.; Meggio, Flavio; Pinna, Lorenzo A.; Rutter, Guy A.

doi:10.1016/j.bbrc.2010.07.035

Cited by 31 publications

(25 citation statements)

References 25 publications

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“…HIPK2 positively influences PDX1 levels and transcriptional activity, and directly phosphorylates the C-terminal portion of PDX1 [28]. HIPK2 is a potential kinase for PDX1 Ser-269, with high glucose concentrations decreasing the degree of phosphorylation on PDX1 Ser-269 in beta cells [42]. We showed that the number of PDX1-positive cells was reduced by 20% in Hipk3-knockout mice on a 12 week high-fat diet (Fig.…”

Section: Discussionmentioning

confidence: 78%

Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice

et al. 2012

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Aims/hypothesis Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes. Here, we focused on a family of serine-threonine kinases known as homeodomain-interacting protein kinases (HIPKs). HIPKs are implicated in the modulation of Wnt signalling, which plays a crucial role in transcriptional activity, and in pancreas development and maintenance. The aim of the present study was to characterise the role of HIPKs in glucose metabolism. Methods We used RNA interference to characterise the role of HIPKs in regulating insulin secretion and transcription activity. We conducted RT-PCR and western blot analyses to analyse the expression and abundance of HIPK genes and proteins in the islets of high-fat diet-fed mice. Glucoseinduced insulin secretion and beta cell proliferation were measured in islets from Hipk3 −/− mice, which have impaired glucose tolerance owing to an insulin secretion deficiency. The abundance of pancreatic duodenal homeobox (PDX)-1 and glycogen synthase kinase (GSK)-3β phosphorylation in Hipk3 −/− islets was determined by immunohistology and western blot analyses.Results We found that HIPKs regulate insulin secretion and transcription activity. Hipk3 expression was most significantly increased in the islets of high-fat diet-fed mice. Furthermore, glucose-induced insulin secretion and beta cell proliferation were decreased in the islets of Hipk3 −/− mice.Levels of PDX1 and GSK-3β phosphorylation were significantly decreased in Hipk3 −/− islets. Conclusions/interpretation Depletion of HIPK3 impairs insulin secretion and glucose tolerance. Decreased levels of HIPK3 may play a substantial role in the pathogenesis of type 2 diabetes.

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Section: Discussionmentioning

confidence: 78%

Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice

et al. 2012

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“…Recently it was shown that HIPK2 is expressed in the developing pancreatic epithelium from E12 to E15 and that its expression is confined preferentially to pancreatic endocrine cells later in development (171). Phosphorylation of the transcription factor, PDX-1, in the C-terminus by HIPK2, possibly at Ser-214 (172), was reported to increase the stability and transcriptional activity of PDX-1 (171). Our own data indicate that HIPK2 posphorylates PDX-1 at Ser-269 in the C-terminal portion of PDX-1 in pancreatic cells in vivo and that phosphorylation at this site leads to nuclear exclusion of PDX-1 and a decrease in PDX-1 target gene expression (172).…”

Section: Homeodomain Interacting Protein Kinase 2 (Hipk2)mentioning

confidence: 99%

“…Phosphorylation of the transcription factor, PDX-1, in the C-terminus by HIPK2, possibly at Ser-214 (172), was reported to increase the stability and transcriptional activity of PDX-1 (171). Our own data indicate that HIPK2 posphorylates PDX-1 at Ser-269 in the C-terminal portion of PDX-1 in pancreatic cells in vivo and that phosphorylation at this site leads to nuclear exclusion of PDX-1 and a decrease in PDX-1 target gene expression (172). As PDX-1 has been shown to directly bind to and regulate the promoter activity of various cell genes, e.g.…”

Section: Homeodomain Interacting Protein Kinase 2 (Hipk2)mentioning

confidence: 99%

Protein Kinases and Pancreatic Islet Function

Xavier¹

2012

Protein Kinases

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“…At least three different post-translational modifications, including phosphorylation, sumoylation and glycosylation, have been suggested to explain nuclear-cytoplasmic shuttling and/or other functions of PDX1 [40][41][42][43][44][45][46]. Phosphorylation is a common post-translational modification implicated in the regulation of numerous transcription factors, but the precise role of PDX1 phosphorylation in the regulation of its subcellular localisation and activity remains unknown [40,41,47].…”

Section: Mst1-pdx1: a Deleterious Interaction Compromising Beta Cell mentioning

confidence: 99%

MST1: a promising therapeutic target to restore functional beta cell mass in diabetes

Ardestani

Maedler

2016

Diabetologia

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The loss of insulin-producing beta cells by apoptosis is a hallmark of all forms of diabetes mellitus. Strategies to prevent beta cell apoptosis and dysfunction are urgently needed to restore the insulin-producing cells and to prevent severe diabetes progression. We recently identified the serine/ threonine kinase known as mammalian sterile 20-like kinase 1 (MST1) as a critical regulator of apoptotic beta cell death and dysfunction. MST1 activates several apoptotic signalling pathways, which further stimulate its own cleavage, leading to a vicious cycle of cell death. This led us to hypothesise that MST1 signalling is central to the initiation of beta cell death in diabetes. We found that MST1 is strongly activated in a diabetic beta cell and induces not only its death but also directly impairs insulin secretion through promoting proteasomal degradation of key beta cell transcription factor, pancreatic and duodenal homeobox 1 (PDX1), which is critical for insulin production.Pre-clinical studies in various animal models of diabetes have reported that MST1 deficiency remarkably restores normoglycaemia and beta cell function and prevents the development of diabetes. Importantly, MST1 deficiency can revert fully diabetic beta cells to a non-diabetic state. MST1 may serve as a target for the development of novel therapies for diabetes that trigger the cause of the disease, namely, the destruction of the beta cells. The major current focus of our investigation is to identify and test the efficacy of potent inhibitors of this death signalling pathway to protect beta cells against the effects of autoimmune attack in type 1 diabetes and to preserve beta cell mass and function in type 2 diabetes. This review summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Heiko Lickert and colleagues,

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Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization

Cited by 31 publications

References 25 publications

Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice

Depletion of homeodomain-interacting protein kinase 3 impairs insulin secretion and glucose tolerance in mice

Protein Kinases and Pancreatic Islet Function

MST1: a promising therapeutic target to restore functional beta cell mass in diabetes

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