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Interaction of the Ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation.

Rad is the prototypic member of a new class of Ras-related GTPases. Purification of the GTPase-activating protein (GAP) for Rad revealed nm23, a putative tumor metastasis suppressor and a development gene in Drosophila. Antibodies against nm23 depleted Rad-GAP activity from human skeletal muscle cytosol, and bacterially expressed nm23 reconstituted the activity. The GAP activity of nm23 was specific for Rad, was absent with the S105N putative dominant negative mutant of Rad, and was reduced with mutations of nm23. In the presence of ATP, GDP.Rad was also reconverted to GTP.Rad by the nucleoside diphosphate (NDP) kinase activity of nm23. Simultaneously, Rad regulated nm23 by enhancing its NDP kinase activity and decreasing its autophosphorylation. Melanoma cells transfected with wild-type Rad, but not the S105N-Rad, showed enhanced DNA synthesis in response to serum; this effect was lost with coexpression of nm23. Thus, the interaction of nm23 and Rad provides a potential novel mechanism for bidirectional, bimolecular regulation in which nm23 stimulates both GTP hydrolysis and GTP loading of Rad whereas Rad regulates activity of nm23. This interaction may play important roles in the effects of Rad on glucose metabolism and the effects of nm23 on tumor metastasis and developmental regulation.

Pubmed ID: 10611312


  • Zhu J
  • Tseng YH
  • Kantor JD
  • Rhodes CJ
  • Zetter BR
  • Moyers JS
  • Kahn CR


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 21, 1999

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK 45935
  • Agency: NCI NIH HHS, Id: R01 CA 37393
  • Agency: NIDDK NIH HHS, Id: R01 DK 47919

Mesh Terms

  • Animals
  • DNA
  • Diabetes Mellitus
  • Enzyme Activation
  • GTP Phosphohydrolases
  • Genes, Tumor Suppressor
  • Glucose
  • Guanosine Triphosphate
  • Humans
  • Immediate-Early Proteins
  • Models, Biological
  • Monomeric GTP-Binding Proteins
  • NM23 Nucleoside Diphosphate Kinases
  • Neoplasm Metastasis
  • Nucleoside-Diphosphate Kinase
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors
  • ras Proteins