Modulation of apoptotic response by LAR family phosphatases-cIAP1 signaling during urinary tract morphogenesis

Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9016-E9025. doi: 10.1073/pnas.1707229114. Epub 2017 Oct 9.

Abstract

The elimination of unwanted cells by apoptosis is necessary for tissue morphogenesis. However, the cellular control of morphogenetic apoptosis is poorly understood, notably the modulation of cell sensitivity to apoptotic stimuli. Ureter maturation, the process by which the ureter is displaced to the bladder wall, represents an exquisite example of morphogenetic apoptosis, requiring the receptor protein tyrosine phosphatases (RPTPs): LAR and RPTPσ. Here we show that LAR-RPTPs act through cellular inhibitor of apoptosis protein 1 (cIAP1) to modulate caspase 3,7-mediated ureter maturation. Pharmacologic or genetic inactivation of cIAP1 reverts the apoptotic deficit of LAR-RPTP-deficient embryos. Moreover, Birc2 (cIAP1) inactivation generates excessive apoptosis leading to vesicoureteral reflux in newborns, which underscores the importance of apoptotic modulation during urinary tract morphogenesis. We finally demonstrate that LAR-RPTP deficiency increases cIAP1 stability during apoptotic cell death. Together these results identify a mode of cIAP1 regulation playing a critical role in the cellular response to apoptotic pathway activation in the embryo.

Keywords: LAR receptor protein tyrosine phosphatases; apoptosis; cIAP1; urinary tract morphogenesis; vesicoureteral reflux.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Embryo, Mammalian
  • Fibroblasts / physiology
  • Gene Expression Regulation, Developmental / physiology*
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases
  • Ureter / embryology*
  • Ureter / metabolism

Substances

  • Inhibitor of Apoptosis Proteins
  • Ubiquitin-Protein Ligases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2
  • Caspase 3