Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP

J Biol Chem. 2004 Jul 9;279(28):28989-97. doi: 10.1074/jbc.M403880200. Epub 2004 Apr 29.


Negative regulation of mitogenic pathways is a fundamental process that remains poorly characterized. The angiotensin II AT2 receptor is a rare example of a 7-transmembrane domain receptor that negatively cross-talks with receptor tyrosine kinases to inhibit cell growth. In the present study, we report the molecular cloning of a novel protein, ATIP1 (AT2-interacting protein), which interacts with the C-terminal tail of the AT2 receptor, but not with those of other receptors such as angiotensin AT1, bradykinin BK2, and adrenergic beta(2) receptor. ATIP1 defines a family of at least four members that possess the same domain of interaction with the AT2 receptor, contain a large coiled-coil region, and are able to dimerize. Ectopic expression of ATIP1 in eukaryotic cells leads to inhibition of insulin, basic fibroblast growth factor, and epidermal growth factor-induced ERK2 activation and DNA synthesis, and attenuates insulin receptor autophosphorylation, in the same way as the AT2 receptor. The inhibitory effect of ATIP1 requires expression, but not ligand activation, of the AT2 receptor and is further increased in the presence of Ang II, indicating that ATIP1 cooperates with AT2 to transinactivate receptor tyrosine kinases. Our findings therefore identify ATIP1 as a novel early component of growth inhibitory signaling cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Division / physiology
  • Chlorocebus aethiops
  • Cloning, Molecular
  • Dimerization
  • Enzyme Activation
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Insulin / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Angiotensin, Type 2 / chemistry
  • Receptor, Angiotensin, Type 2 / genetics
  • Receptor, Angiotensin, Type 2 / metabolism*
  • Sequence Alignment
  • Signal Transduction*
  • Tissue Distribution
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Two-Hybrid System Techniques


  • Carrier Proteins
  • Insulin
  • MTUS1 protein, human
  • Mtus1 protein, mouse
  • Receptor, Angiotensin, Type 2
  • Tumor Suppressor Proteins
  • Fibroblast Growth Factor 2
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase 1

Associated data

  • GENBANK/AF173380
  • GENBANK/AF293357