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Autoinhibition of Bcr-Abl through its SH3 domain.

Abstract：

:Bcr-Abl is a dysregulated tyrosine kinase whose mechanism of activation is unclear. Here, we demonstrate that, like c-Abl, Bcr-Abl is negatively regulated through its SH3 domain. Kinase activity, transformation, and leukemogenesis by Bcr-Abl are greatly impaired by mutations of the Bcr coiled-coil domain that disrupt oligomerization, but restored by an SH3 point mutation that blocks ligand binding or a complementary mutation at the intramolecular SH3 binding site defined in c-Abl. Phosphorylation of tyrosines in the activation loop of the catalytic domain and the linker between the SH2 and catalytic domains (SH2-CD linker) is dependent on oligomerization and required for leukemogenesis. These results suggest that Bcr-Abl has a monomeric, unphosphorylated state with the SH3 domain engaged intramolecularly to Pro1124 in the SH2-CD linker, the form that is sensitive to the inhibitor imatinib (STI-571). The sole function of the coiled-coil domain is to disrupt the autoinhibited conformation through oligomerization and intermolecular autophosphorylation.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Smith KM,Yacobi R,Van Etten RA

doi

10.1016/s1097-2765(03)00274-0

subject

Has Abstract

pub_date

2003-07-01 00:00:00

pages

27-37

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(03)00274-0

journal_volume

12

pub_type

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