The A-kinase Anchoring Protein GSKIP Regulates GSK3β Activity and Controls Palatal Shelf Fusion in Mice

J Biol Chem. 2016 Jan 8;291(2):681-90. doi: 10.1074/jbc.M115.701177. Epub 2015 Nov 18.

Abstract

A-kinase anchoring proteins (AKAPs) represent a family of structurally diverse proteins, all of which bind PKA. A member of this family is glycogen synthase kinase 3β (GSK3β) interaction protein (GSKIP). GSKIP interacts with PKA and also directly interacts with GSK3β. The physiological function of the GSKIP protein in vivo is unknown. We developed and characterized a conditional knock-out mouse model and found that GSKIP deficiency caused lethality at birth. Embryos obtained through Caesarean section at embryonic day 18.5 were cyanotic, suffered from respiratory distress, and failed to initiate breathing properly. Additionally, all GSKIP-deficient embryos showed an incomplete closure of the palatal shelves accompanied by a delay in ossification along the fusion area of secondary palatal bones. On the molecular level, GSKIP deficiency resulted in decreased phosphorylation of GSK3β at Ser-9 starting early in development (embryonic day 10.5), leading to enhanced GSK3β activity. At embryonic day 18.5, GSK3β activity decreased to levels close to that of wild type. Our findings reveal a novel, crucial role for GSKIP in the coordination of GSK3β signaling in palatal shelf fusion.

Keywords: A-kinase anchoring protein (AKAP); GSK3β interaction protein; animal model; cell signaling; cleft palate; cyclic AMP (cAMP); development; glycogen synthase kinase 3 (GSK-3); protein kinase A (PKA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cleft Palate / embryology
  • Cleft Palate / enzymology
  • Cleft Palate / pathology
  • Embryo Loss / metabolism
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / enzymology
  • Female
  • Gene Expression Regulation, Developmental
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Hemizygote
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Palate / abnormalities
  • Palate / embryology*
  • Palate / enzymology
  • Palate / metabolism*
  • Phenotype
  • Phosphorylation
  • Phosphoserine / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / deficiency
  • Repressor Proteins / metabolism*
  • Respiration

Substances

  • GSKIP protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • Phosphoserine
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3