ABL SH3 mutant inhibits BCR-ABL activity and increases imatinib sensitivity by targeting RIN1 protein in CML cell

Cancer Letters
Xin LiuWenli Feng

Abstract

SH3 domain plays an important role in maintaining autoinhibition of BCR-ABL protein. RIN1 interacts with BCR-ABL SH3 domain via PxxP motifs to promote autophosphorylation as well as activation of BCR-ABL tyrosine kinase, suggesting using exogenous SH3 domain which blocks the interaction of BCR-ABL and RIN1 could be an adjunct therapy for CML. Here, we reported a novel p-BCR-ABL inhibitor, designed as ABL SH3 mutant, and identified its effects on inhibiting the tyrosine kinase activity of BCR-ABL without or with imatinib (IM) in vitro and in vivo. Our results demonstrated that ABL SH3 mutant T79Y markedly repressed the expression of BCR-ABL signaling pathways in IM-resistant cell lines KCL22 and K562/G01 as well as IM-sensitive cell line K562. Moreover, combination of T79Y with IM considerably decreased the proliferation of leukemia cells in vivo. Inhibition of BCR-ABL and RIN1 interaction using exogenous modified BCR-ABL SH3 domain provides a feasible and alternative option of small molecule inhibitors for CML treatment.

References

Sep 18, 1992·Cell·C L SawyersO N Witte
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
May 13, 1997·Proceedings of the National Academy of Sciences of the United States of America·L HanJ Colicelli
Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
Jan 7, 2004·Nature Reviews. Molecular Cell Biology·Oliver Hantschel, Giulio Superti-Furga
Mar 23, 2005·Cancer Research·Michael G Kharas, David A Fruman
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jun 4, 2010·Blood·Daniel W SherbenouMichael W Deininger
Jun 11, 2011·The Journal of Biological Chemistry·Andrew S DixonCarol S Lim
Dec 6, 2011·Molecular Pharmaceutics·Andrew S DixonCarol S Lim
May 19, 2012·Nucleic Acids Research·Leonardo G TrabucoRobert B Russell
Jan 15, 2013·The Journal of Biological Chemistry·Shoghag PanjarianThomas E Smithgall

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.