Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.
Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.
Dai
Z
Z
Department of Pharmacology and Cancer Biology and Division of Hematology-Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.michael.stern@yale.edu
Quackenbush
R C
RC
Courtney
K D
KD
Grove
M
M
Cortez
D
D
Reuther
G W
GW
Pendergast
A M
AM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
C513733:ABI1 protein, human; C096831:ABI2 protein, human; C513734:Abi1 protein, mouse; C490756:Abi2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D014452:Ubiquitins; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D016392:Proto-Oncogene Proteins pp60(c-src); D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins