title: Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Los Angeles, 90095, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Afar
authors.forename: L
authors.initials: L
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: McLaughlin
authors.forename: S
authors.initials: S
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Dhaka
authors.forename: K
authors.initials: K
authors.lastname: Parmar
authors.forename: N
authors.initials: N
authors.lastname: Rosenberg
authors.forename: O N
authors.initials: ON
authors.lastname: Witte
authors.forename: J
authors.initials: J
authors.lastname: Colicelli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006410:Hematopoiesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007942:Leukemia, Experimental / Q000235:genetics / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D020691:rab GTP-Binding Proteins; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D011506:Proteins; C092117:RIN1 protein, human; C490451:Rin1 protein, mouse; D019000:Phosphotyrosine; D016044:Fusion Proteins, bcr-abl; D020691:rab GTP-Binding Proteins