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Title: c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution

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Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 0006-2960
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 55; Journal Issue: 23
Country of Publication:
United States

Citation Formats

Badger, John, Grover, Prerna, Shi, Haibin, Panjarian, Shoghag B., Engen, John R., Smithgall, Thomas E., and Makowski, Lee. c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution. United States: N. p., 2016. Web. doi:10.1021/acs.biochem.6b00202.
Badger, John, Grover, Prerna, Shi, Haibin, Panjarian, Shoghag B., Engen, John R., Smithgall, Thomas E., & Makowski, Lee. c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution. United States. doi:10.1021/acs.biochem.6b00202.
Badger, John, Grover, Prerna, Shi, Haibin, Panjarian, Shoghag B., Engen, John R., Smithgall, Thomas E., and Makowski, Lee. Tue . "c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution". United States. doi:10.1021/acs.biochem.6b00202.
title = {c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution},
author = {Badger, John and Grover, Prerna and Shi, Haibin and Panjarian, Shoghag B. and Engen, John R. and Smithgall, Thomas E. and Makowski, Lee},
abstractNote = {},
doi = {10.1021/acs.biochem.6b00202},
journal = {Biochemistry},
number = 23,
volume = 55,
place = {United States},
year = {Tue Jun 14 00:00:00 EDT 2016},
month = {Tue Jun 14 00:00:00 EDT 2016}
  • c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks aphosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but withmore » specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571)to inhibit the catalytic activity of Abl, but not that of c-Src.« less
  • The non-receptor-type tyrosine kinase c-Abl is involved in actin dynamics in the cytoplasm. Having three nuclear localization signals (NLSs) and one nuclear export signal, c-Abl shuttles between the nucleus and the cytoplasm. Although monomeric actin and filamentous actin (F-actin) are present in the nucleus, little is known about the relationship between c-Abl and nuclear actin dynamics. Here, we show that nuclear-localized c-Abl induces nuclear F-actin formation. Adriamycin-induced DNA damage together with leptomycin B treatment accumulates c-Abl into the nucleus and increases the levels of nuclear F-actin. Treatment of c-Abl-knockdown cells with Adriamycin and leptomycin B barely increases the nuclear F-actinmore » levels. Expression of nuclear-targeted c-Abl (NLS-c-Abl) increases the levels of nuclear F-actin even without Adriamycin, and the increased levels of nuclear F-actin are not inhibited by inactivation of Abl kinase activity. Intriguingly, expression of NLS-c-Abl induces the formation of long and winding bundles of F-actin within the nucleus in a c-Abl kinase activity-dependent manner. Furthermore, NLS-c-AblΔC, which lacks the actin-binding domain but has the full tyrosine kinase activity, is incapable of forming nuclear F-actin and in particular long and winding nuclear F-actin bundles. These results suggest that nuclear c-Abl plays critical roles in actin dynamics within the nucleus. - Highlights: • We show the involvement of c-Abl tyrosine kinase in nuclear actin dynamics. • Nuclear F-actin is formed by nuclear-localized c-Abl and its kinase-dead version. • The c-Abl actin-binding domain is prerequisite for nuclear F-actin formation. • Formation of long nuclear F-actin bundles requires nuclear c-Abl kinase activity. • We discuss a role for nuclear F-actin bundle formation in chromatin regulation.« less
  • RBM39, also known as splicing factor HCC1.4, acts as a transcriptional coactivator for the steroid nuclear receptors JUN/AP-1, ESR1/ER-α and ESR2/ER-β. RBM39 is involved in the regulation of the transcriptional responses of these steroid nuclear receptors and promotes transcriptional initiation. In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl wasmore » shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. The results suggest that mammalian c-Abl plays an important role in steroid hormone receptor-mediated transcription by regulating RBM39. - Highlights: • c-Abl interacts with RBM39. • RBM39 is phosphorylated by c-Abl. • c-Abl regulates transcriptional coactivation activity of RBM39 on the ERα and PRβ.« less
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