Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD.

Blood
Jennifer L RocnikD Gary Gilliland

Abstract

Acquired mutations in the FLT3 receptor tyrosine kinase are common in acute myeloid leukemia and result in constitutive activation. The most frequent mechanism of activation is disruption of the juxtamembrane autoregulatory domain by internal tandem duplications (ITDs). FLT3-ITDs confer factor-independent growth to hematopoietic cells and induce a myeloproliferative syndrome in murine bone marrow transplant models. We and others have observed that FLT3-ITD activates STAT5 and its downstream effectors, whereas ligand-stimulated wild-type FLT3 (FLT3WT) does not. In vitro mapping of tyrosine phosphorylation sites in FLT3-ITD identified 2 candidate STAT5 docking sites within the juxtamembrane domain that are disrupted by the ITD. Tyrosine to phenylalanine substitution of residues 589 and 591 in the context of the FLT3-ITD did not affect tyrosine kinase activity, but abrogated STAT5 activation. Furthermore, FLT3-ITD-Y589/591F was incapable of inducing a myeloproliferative phenotype when transduced into primary murine bone marrow cells, whereas FLT3-ITD induced myeloproliferative disease with a median latency of 50 days. Thus, the conformational change in the FLT3 juxtamembrane domain induced by the ITD activates the kinase through d...Continue Reading

References

Nov 1, 1992·Biochimie·V OllendorffO deLapeyrière
Oct 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·W MatthewsI R Lemischka
Jun 27, 1998·The Journal of Biological Chemistry·R M BaxterA Kazlauskas
Oct 12, 2000·Biochemical and Biophysical Research Communications·S Zhang, H E Broxmeyer
Aug 15, 2002·Blood·D Gary Gilliland, James D Griffin
Feb 5, 2004·Molecular Cell·James GriffithKumkum Saxena
Apr 7, 2004·Proceedings of the National Academy of Sciences of the United States of America·Yuki KimuraAlan Bernstein
Sep 6, 2005·Cancer Research·Mark LivingstoneThanos D Halazonetis

❮ Previous
Next ❯

Citations

Jan 13, 2010·Annals of Hematology·Ellen Christina ObermannAlexandar Tzankov
Jul 10, 2010·Nature Medicine·Michael G KharasGeorge Q Daley
Sep 11, 2010·The Journal of Biological Chemistry·Josefine ÅhsbergMikael Sigvardsson
Dec 8, 2010·The Journal of Biological Chemistry·Amandine ChaixPaulo De Sepulveda
Jan 26, 2011·The Journal of Biological Chemistry·Deepika AroraJörg P Müller
Jun 25, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Soheil Meshinchi, Frederick R Appelbaum
Feb 5, 2008·The Journal of Clinical Investigation·Wenbin XiaoToshiaki Kawakami
Jul 17, 2012·The Journal of Clinical Investigation·Hanna S RadomskaDaniel G Tenen
Mar 16, 2007·Blood·Chunaram ChoudharyHubert Serve
Jan 16, 2009·Blood·Frank BreitenbuecherThomas Fischer
Feb 29, 2008·Blood·Soheil MeshinchiJerald P Radich
Sep 4, 2012·Blood·De-Chen LinH Phillip Koeffler
May 3, 2012·Journal of Leukocyte Biology·Haiyan S Li, Stephanie S Watowich
May 10, 2011·PloS One·Ting-lei GuRoberto D Polakiewicz
Aug 13, 2013·Leukemia Research and Treatment·Ugo Testa, Elvira Pelosi
Apr 1, 2014·Current Hematologic Malignancy Reports·Akshay Sudhindra, Catherine Choy Smith
Dec 12, 2012·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Tomas KupsaLadislav Jebavy
Jan 6, 2007·Leukemia·D AuclairS M Wilhelm
Jul 14, 2010·Oncogene·E WeisbergJ D Griffin
Jun 23, 2012·Leukemia & Lymphoma·Olga BlauIgor Wolfgang Blau
Sep 28, 2013·Expert Opinion on Investigational Drugs·Fabiana Ostronoff, Elihu Estey
May 27, 2009·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ellen WeisbergJames D Griffin
Apr 7, 2009·Biochemical and Biophysical Research Communications·Hoang Anh VuYuko Sato
Aug 12, 2008·Seminars in Oncology·Claudia SchollStefan Fröhling
May 15, 2009·British Journal of Haematology·Kristina MassonLars Rönnstrand
Mar 26, 2010·Archiv der Pharmazie·Matthias RabillerDaniel Rauh

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.