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Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1.

The growth arrest and DNA damage-inducible protein, GADD34, was identified by its interaction with human inhibitor 1 (I-1), a protein kinase A (PKA)-activated inhibitor of type 1 protein serine/threonine phosphatase (PP1), in a yeast two-hybrid screen of a human brain cDNA library. Recombinant GADD34 (amino acids 233 to 674) bound both PKA-phosphorylated and unphosphorylated I-1(1-171). Serial truncations mapped the C terminus of I-1 (amino acids 142 to 171) as essential for GADD34 binding. In contrast, PKA phosphorylation was required for PP1 binding and inhibition by the N-terminal I-1(1-80) fragment. Pulldowns of GADD34 proteins expressed in HEK293T cells showed that I-1 bound the central domain of GADD34 (amino acids 180 to 483). By comparison, affinity isolation of cellular GADD34/PP1 complexes showed that PP1 bound near the C terminus of GADD34 (amino acids 483 to 619), a region that shows sequence homology with the virulence factors ICP34.5 of herpes simplex virus and NL-S of avian sarcoma virus. While GADD34 inhibited PP1-catalyzed dephosphorylation of phosphorylase a, the GADD34-bound PP1 was an active eIF-2alpha phosphatase. In brain extracts from active ground squirrels, GADD34 bound both I-1 and PP1 and eIF-2alpha was largely dephosphorylated. In contrast, the I-1/GADD34 and PP1/GADD34 interactions were disrupted in brain from hibernating animals, in which eIF-2alpha was highly phosphorylated at serine-51 and protein synthesis was inhibited. These studies suggested that modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues.

Pubmed ID: 11564868


  • Connor JH
  • Weiser DC
  • Li S
  • Hallenbeck JM
  • Shenolikar S


Molecular and cellular biology

Publication Data

October 20, 2001

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK52054

Mesh Terms

  • Animals
  • Antigens, Differentiation
  • Apoptosis
  • Brain
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases
  • DNA Damage
  • DNA, Complementary
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • Endoribonucleases
  • Gene Library
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Models, Genetic
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Plant Proteins
  • Precipitin Tests
  • Protein Binding
  • Protein Phosphatase 1
  • Proteins
  • RNA-Binding Proteins
  • Recombinant Proteins
  • Sciuridae
  • Signal Transduction
  • Two-Hybrid System Techniques