Phosphorylation at tyrosine 262 promotes GADD34 protein turnover.

Journal Article (Journal Article)

In mammalian cells, metabolic and environmental stress increases the phosphorylation of the eukaryotic translational initiation factor, eIF2α, and attenuates global protein synthesis. Subsequent transcriptional activation of GADD34 assembles an eIF2α phosphatase that feeds back to restore mRNA translation. Active proteasomal degradation of GADD34 protein then reestablishes the sensitivity of cells to subsequent bouts of stress. Mass spectrometry established GADD34 phosphorylation on multiple serines, threonines, and tyrosines. Phosphorylation at tyrosine 262 enhanced the rate of the GADD34 protein turnover. Substrate-trapping studies identified TC-PTP (PTPN2) as a potential GADD34 phosphatase, recognizing phosphotyrosine 262. Reduced GADD34 protein levels in TC-PTP-null MEFs following ER stress emphasized the importance of TC-PTP in determining the cellular levels of GADD34 protein. The susceptibility of TC-PTP-null MEFs to ER stress-induced apoptosis was significantly ameliorated by ectopic expression of GADD34. The data suggested that GADD34 phosphorylation on tyrosine 262 modulates endoplasmic reticulum stress signaling and cell fate.

Full Text

Duke Authors

Cited Authors

  • Zhou, W; Jeyaraman, K; Yusoff, P; Shenolikar, S

Published Date

  • November 15, 2013

Published In

Volume / Issue

  • 288 / 46

Start / End Page

  • 33146 - 33155

PubMed ID

  • 24092754

Pubmed Central ID

  • PMC3829162

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M113.504407


  • eng

Conference Location

  • United States