Regulation of the Oncogenic Activity of BCR-ABL by a Tightly Bound Substrate Protein RIN1

Immunity. 1997 Jun;6(6):773-82. doi: 10.1016/s1074-7613(00)80452-5.

Abstract

RIN1 was originally identified by its ability to physically bind to and interfere with activated Ras in yeast. Paradoxically, RIN1 potentiates the oncogenic activity of the BCR-ABL tyrosine kinase in hematopoietic cells and dramatically accelerates BCR-ABL-induced leukemias in mice. RIN1 rescues BCR-ABL mutants for transformation in a manner distinguishable from the cell cycle regulators c-Myc and cyclin D1 and the Ras connector Shc. These biological effects require tyrosine phosphorylation of RIN1 and binding of RIN1 to the Abl-SH2 and SH3 domains. RIN1 is tyrosine phosphorylated and is associated with BCR-ABL in human and murine leukemic cells. RIN1 exemplifies a new class of effector molecules dependent on the concerted action of the SH3, SH2, and catalytic domains of a cytoplasmic tyrosine kinase.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Carrier Proteins / physiology*
  • Cell Division
  • Cell Transformation, Neoplastic / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • GRB2 Adaptor Protein
  • Hematopoiesis
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / pathology
  • Macromolecular Substances
  • Mice
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Proteins / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Survival Analysis
  • Tumor Cells, Cultured
  • rab GTP-Binding Proteins*
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Macromolecular Substances
  • Proteins
  • RIN1 protein, human
  • Rin1 protein, mouse
  • Phosphotyrosine
  • Fusion Proteins, bcr-abl
  • rab GTP-Binding Proteins