Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1.
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.
Afar
D E
DE
Department of Microbiology and Molecular Genetics, University of California, Los Angeles, 90095, USA.
Han
L
L
McLaughlin
J
J
Wong
S
S
Dhaka
A
A
Parmar
K
K
Rosenberg
N
N
Witte
O N
ON
Colicelli
J
J
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
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