Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation

Cell. 1991 Mar 22;64(6):1057-68. doi: 10.1016/0092-8674(91)90261-v.


We isolated a cDNA encoding a functional human thrombin receptor by direct expression cloning in Xenopus oocytes. mRNA encoding this receptor was detected in human platelets and vascular endothelial cells. The deduced amino acid sequence revealed a new member of the seven transmembrane domain receptor family with a large amino-terminal extracellular extension containing a remarkable feature. A putative thrombin cleavage site (LDPR/S) resembling the activation cleavage site in the zymogen protein C (LDPR/I) was noted 41 amino acids carboxyl to the receptor's start methionine. A peptide mimicking the new amino terminus created by cleavage at R41 was a potent agonist for both thrombin receptor activation and platelet activation. "Uncleavable" mutant thrombin receptors failed to respond to thrombin but were responsive to the new amino-terminal peptide. These data reveal a novel signaling mechanism in which thrombin cleaves its receptor's amino-terminal extension to create a new receptor amino terminus that functions as a tethered ligand and activates the receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood Platelets / metabolism
  • Cell Line
  • Cloning, Molecular
  • Endothelium / metabolism
  • Humans
  • Megakaryocytes / metabolism
  • Microinjections
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oocytes / metabolism
  • Peptide Fragments / metabolism
  • Platelet Activation / physiology*
  • Poly A / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / physiology
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Thrombin
  • Thrombin / physiology*
  • Xenopus laevis


  • Peptide Fragments
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Thrombin
  • Poly A
  • Thrombin

Associated data

  • GENBANK/M62424
  • GENBANK/S63143
  • GENBANK/S63144
  • GENBANK/S63145
  • GENBANK/S63146
  • GENBANK/S63147
  • GENBANK/S63148
  • GENBANK/S66577
  • GENBANK/S71189
  • GENBANK/X62953