title: Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling.
abstract: The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family of E3 ubiquitin ligases. SOCS2 is known to regulate signal transduction by cytokine receptors and receptor tyrosine kinases. The receptor tyrosine kinase FLT3 is of importance for proliferation, survival and differentiation of hematopoietic cells and is frequently mutated in acute myeloid leukemia. We observed that SOCS2 associates with activated FLT3 through phosphotyrosine residues 589 and 919, and co-localizes with FLT3 in the cell membrane. SOCS2 increases FLT3 ubiquitination and accelerates receptor degradation in proteasomes. SOCS2 negatively regulates FLT3 signaling by blocking activation of Erk 1/2 and STAT5. Furthermore, SOCS2 expression leads to a decrease in FLT3-ITD-mediated cell proliferation and colony formation. Thus, we suggest that SOCS2 associates with activated FLT3 and negatively regulates the FLT3 signaling pathways.
authors.affiliation: Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Wallenberg Laboratory, Skåne University Hospital, 20502 Malmö, Sweden.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000378:metabolism*
chemical_list: C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D019000:Phosphotyrosine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
references.citation: J Biol Chem. 2003 Mar 14;278(11):9159-66
references.pmid: 12511554
references.citation: Genomics. 2001 Mar 1;72(2):209-12
references.pmid: 11401434
references.citation: Blood. 2009 Apr 9;113(15):3568-76
references.pmid: 19204327
references.citation: EMBO J. 1996 Oct 1;15(19):5299-313
references.pmid: 8895575
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7637-42
references.pmid: 16675548
references.citation: Leukemia. 2003 Sep;17(9):1738-52
references.pmid: 12970773
references.citation: Blood. 2006 Sep 1;108(5):1542-50
references.pmid: 16684964
references.citation: Leukemia. 2008 Dec;22(12):2169-75
references.pmid: 18769447
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2175-80
references.pmid: 11854514
references.citation: Genes Dev. 2004 Dec 1;18(23):2861-6
references.pmid: 15574592
references.citation: Exp Hematol. 2009 Aug;37(8):979-89
references.pmid: 19477218
references.citation: Br J Haematol. 2009 Jul;146(2):193-202
references.pmid: 19438505
references.citation: Mol Oncol. 2013 Jun;7(3):693-703
references.pmid: 23548639
references.citation: Cell Signal. 2009 Dec;21(12):1717-26
references.pmid: 19540337
references.citation: J Clin Invest. 2005 Feb;115(2):397-406
references.pmid: 15690087
references.citation: EMBO J. 1993 Nov;12(11):4199-209
references.pmid: 7693453
references.citation: PLoS One. 2012;7(12):e53509
references.pmid: 23300935
references.citation: Blood. 2012 Oct 18;120(16):3310-7
references.pmid: 22942183
references.citation: Clin Cancer Res. 2012 Jan 1;18(1):127-39
references.pmid: 22090359
references.citation: J Biol Chem. 2012 Oct 19;287(43):36509-17
references.pmid: 22952242
references.citation: J Biol Chem. 2004 Mar 26;279(13):12249-59
references.pmid: 14707129
references.citation: PLoS One. 2012;7(6):e38384
references.pmid: 22693634
references.citation: EMBO J. 1999 Feb 15;18(4):904-15
references.pmid: 10022833
references.citation: J Biol Chem. 2011 Jan 7;286(1):480-90
references.pmid: 21030588
references.citation: Nat Cell Biol. 2001 May;3(5):460-5
references.pmid: 11331873
references.citation: Clin Cancer Res. 2003 Jun;9(6):2140-50
references.pmid: 12796379
references.citation: Blood. 2007 Jul 1;110(1):370-4
references.pmid: 17356133
references.citation: Mol Oncol. 2013 Jun;7(3):402-18
references.pmid: 23246379
references.citation: PLoS One. 2011;6(9):e25358
references.pmid: 21980433
references.citation: Blood. 2012 Aug 23;120(8):1691-702
references.pmid: 22517899
references.citation: Exp Cell Res. 2003 Aug 1;288(1):110-8
references.pmid: 12878163
references.citation: Nat Rev Immunol. 2007 Jun;7(6):454-65
references.pmid: 17525754
references.citation: J Biol Chem. 2003 Aug 22;278(34):31972-9
references.pmid: 12783885