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.
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 .
What kind of enzyme is encoded by the proto-oncogene ABL1?
What kind of enzyme is encoded by the proto - oncogene ABL1 ?
Protein-Tyrosine Kinase
Nonreceptor tyrosine kinase Protein-Tyrosine Kinase protein tyrosine kinase