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

Biochemical and Biophysical Research Communications
R AnG A Rutter

Abstract

Pancreatic and duodenal homeobox 1 (PDX1) regulates pancreatic development and mature beta-cell function. We demonstrate by mass spectrometry that serine residue at position 269 in the C-terminal domain of PDX1 is phosphorylated in beta-cells. Besides we show that the degree of phosphorylation, assessed with a phospho-Ser-269-specific antibody, is decreased by elevated glucose concentrations in both MIN6 beta-cells and primary mouse pancreatic islets. Homeodomain interacting protein kinase 2 (HIPK2) phosphorylates PDX1 in vitro; phosphate incorporation substantially decreases in PDX1 S269A mutant. Silencing of HIPK2 led to a 51+/-0.2% decrease in Ser-269 phosphorylation in MIN6 beta-cells. Mutation of Ser-269 to phosphomimetic residue glutamic acid (S269E) or de-phosphomimetic residue alanine (S269A) exerted no effect on PDX1 half-life. Instead, PDX1 S269E mutant displayed abnormal changes in subnuclear localization in response to high glucose. Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell...Continue Reading

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Citations

Oct 16, 2013·The International Journal of Biochemistry & Cell Biology·Sabrina WelkerMathias Montenarh
Jul 22, 2014·Journal of Tissue Engineering and Regenerative Medicine·Akram MansouriEsmaeil Ebrahimie
Apr 8, 2016·Diabetologia·Amin Ardestani, Kathrin Maedler
Feb 15, 2015·The International Journal of Biochemistry & Cell Biology·Lisa SchwindMathias Montenarh
Dec 31, 2016·Pharmaceuticals·Sabrina KleinClaudia Götz
Sep 22, 2017·International Journal of Molecular Sciences·Zhihua Du, Vladimir N Uversky
Sep 11, 2019·International Journal of Molecular Sciences·Emmanuel AmpofoClaudia Götz
Mar 7, 2021·International Journal of Molecular Sciences·Eva Louise SteinmetzUwe Walldorf
Sep 13, 2020·Molecular and Cellular Endocrinology·Danny Hon Fai SoKwok-Ming Yao

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Methods Mentioned

BETA
PCR
transfection

Software Mentioned

BLAST
AdEasy

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