An intramolecular SH3-domain interaction regulates c-Abl activity.
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase (c-Abl) that has been implicated in processes of cell differentiation, cell division, cell adhesion and stress response. Alterations of ABL1 by chromosomal rearrangement or viral transduction can lead to malignant transformation. Activity of the c-Abl protein is negatively regulated by its SH3 domain through an unknown mechanism, and deletion of the SH3 domain turns ABL1 into an oncogene. We present evidence for an intramolecular inhibitory interaction of the SH3 domain with the catalytic domain and with the linker between the SH2 and catalytic domain (SH2-CD linker). Site-directed mutations in each of these three elements activate c-Abl. Mutations in the linker cause a conformational change of the molecule and increase binding of the SH3 domain to peptide ligands. Individual mutation of two charged residues in the SH3 and catalytic domain activates c-Abl, while inhibition is restored in the double reciprocal mutant. We propose that regulators of c-Abl will have opposite effects on its activity depending on their ability to favour or disrupt these intramolecular interactions.
Barilá
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European Molecular Biology Laboratory, Heidelberg, Germany.
Superti-Furga
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G
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology*
C000715470:MAS1 protein, human; D010455:Peptides; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl