Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-alpha

Nature. 1999 Oct 7;401(6753):606-10. doi: 10.1038/44170.


Protein-tyrosine phosphatases (PTPs) are vital for regulating tryosine phosphorylation in many processes, including growth and differentiation. The regulation of receptor-like PTP (RPTP) activity remains poorly understood, but based on the crystal structure of RPTPalpha domain 1 we have proposed that dimerization can negatively regulate activity, through the interaction of an inhibitory 'wedge' on one monomer with the catalytic cleft of domain 1 in the other monomer. Here we show that dimerization inhibits the activity of a full-length RPTP in vivo. We generated stable disulphide-bonded full-length RPTPalpha homodimers by expressing mutants with single cysteines at different positions in the ectodomain juxtamembrane region. Expression of wild-type RPTPalpha and Phe135Cys and Thr141Cys mutants in RPTPalpha-null mouse embryo cells increased dephosphorylation and activity of Tyr 529 in the protein tyrosine kinase c-Src; in contrast, expression of a Pro137Cys mutant did not. Mutation of Pro 210/211 to leucine in the inhibitory wedge of the Pro137Cys mutant restored its ability to activate c-Src, indicating that dimerization may inhibit full-length RPTPalpha activity in a manner stereochemically consistent with RPTPalpha crystal structures. Our results suggest that RPTPalpha activity can in principle be negatively regulated by dimerization in vivo.

Publication types

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

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Catalysis
  • Cell Line
  • Cell Membrane / enzymology
  • Dimerization
  • Disulfides / metabolism
  • Mice
  • Mutagenesis, Site-Directed
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4
  • Receptors, Cell Surface*
  • Transfection
  • src-Family Kinases


  • Disulfides
  • Receptors, Cell Surface
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • Protein Tyrosine Phosphatases
  • Ptpra protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4