Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis

J Biol Chem. 2017 Nov 3;292(44):18091-18097. doi: 10.1074/jbc.M117.797613. Epub 2017 Sep 14.


Glycoprotein A repetitions predominant (GARP) (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGFβ. However, GARP's role in organ development in mammalian systems is unclear. To determine the function of GARP in vivo, we generated a GARP KO mouse model. Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs. Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling pathway in the GARP-null developing palates. Of note, the failure to develop the secondary palate and concurrent reduction of SMAD phosphorylation without other defects in GARP KO mice phenocopied TGFβ3 KO mice, although GARP has not been suggested previously to interact with TGFβ3. We found that GARP and TGFβ3 co-localize in medial edge epithelial cells at E14.5. In vitro studies confirmed that GARP and TGFβ3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGFβ3. Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGFβ3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of GARP in positively regulating TGFβ3 activation and function.

Keywords: GARP, palatogenesis; TGFβ; apoptosis; cell signaling; development; embryo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Cleft Palate / embryology
  • Cleft Palate / metabolism
  • Cleft Palate / pathology
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Female
  • Gene Expression Regulation, Developmental*
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Knockout
  • Organogenesis*
  • Palate / abnormalities
  • Palate / embryology
  • Palate / metabolism*
  • Palate / pathology
  • Phosphorylation
  • Pregnancy
  • Protein Multimerization
  • Protein Processing, Post-Translational*
  • Protein Transport
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Transforming Growth Factor beta3 / agonists*
  • Transforming Growth Factor beta3 / chemistry
  • Transforming Growth Factor beta3 / genetics
  • Transforming Growth Factor beta3 / metabolism


  • Lrrc32 protein, mouse
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Tgfb3 protein, mouse
  • Transforming Growth Factor beta3