title: SHP2 phosphatase promotes mast cell chemotaxis toward stem cell factor via enhancing activation of the Lyn/Vav/Rac signaling axis.
abstract: SHP2 protein-tyrosine phosphatase (encoded by Ptpn11) positively regulates KIT (CD117) signaling in mast cells and is required for mast cell survival and homeostasis in mice. In this study, we uncover a role of SHP2 in promoting chemotaxis of mast cells toward stem cell factor (SCF), the ligand for KIT receptor. Using an inducible SHP2 knockout (KO) bone marrow-derived mast cell (BMMC) model, we observed defects in SCF-induced cell spreading, polarization, and chemotaxis. To address the mechanisms involved, we tested whether SHP2 promotes activation of Lyn kinase that was previously shown to promote mast cell chemotaxis. In SHP2 KO BMMCs, SCF-induced phosphorylation of the inhibitory C-terminal residue (pY507) was elevated compared with control cells, and phosphorylation of activation loop (pY396) was diminished. Because Lyn also was detected by substrate trapping assays, these results are consistent with SHP2 activating Lyn directly by dephosphorylation of pY507. Further analyses revealed a SHP2- and Lyn-dependent pathway leading to phosphorylation of Vav1, Rac activation, and F-actin polymerization in SCF-treated BMMCs. Treatment of BMMCs with a SHP2 inhibitor also led to impaired chemotaxis, consistent with SHP2 promoting SCF-induced chemotaxis of mast cells via a phosphatase-dependent mechanism. Thus, SHP2 inhibitors may be useful to limit SCF/KIT-induced mast cell recruitment to inflamed tissues or the tumor microenvironment.
authors.affiliation: Division of Cancer Biology and Genetics, Department of Biomedical and Molecular Sciences, Queen's University, Queen's Cancer Research Institute, Kingston, Ontario K7L 3N6, Canada;
authors.forename: Namit
authors.initials: N
authors.lastname: Sharma
authors.forename: Stephanie
authors.initials: S
authors.lastname: Everingham
authors.forename: Baskar
authors.initials: B
authors.lastname: Ramdas
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Andrew W B
authors.initials: AW
authors.lastname: Craig
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000276:immunology*; D019089:Stem Cell Factor / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D019089:Stem Cell Factor; C496619:Vav1 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
references.citation: EMBO J. 1995 Jan 16;14(2):257-65
references.pmid: 7530656
references.citation: Biochim Biophys Acta. 2007 Sep;1773(9):1407-15
references.pmid: 17560670
references.citation: Immunol Rev. 2009 Mar;228(1):149-69
references.pmid: 19290926
references.citation: Mol Cell Biol. 2011 Oct;31(19):4052-62
references.pmid: 21791602
references.citation: J Immunol. 2006 Feb 15;176(4):2421-9
references.pmid: 16456001
references.citation: Immunity. 2000 May;12(5):557-68
references.pmid: 10843388
references.citation: J Biol Chem. 2008 Oct 24;283(43):29175-85
references.pmid: 18725415
references.citation: J Immunol. 2012 Jun 1;188(11):5428-37
references.pmid: 22529299
references.citation: J Biol Chem. 2013 Apr 12;288(15):10472-82
references.pmid: 23457302
references.citation: Cell Signal. 2008 Mar;20(3):453-9
references.pmid: 17993263
references.citation: Mol Cell Biol. 2012 Jul;32(14):2653-63
references.pmid: 22566685
references.citation: Dev Cell. 2010 May 18;18(5):750-62
references.pmid: 20493809
references.citation: Blood. 2003 Jun 15;101(12):4725-32
references.pmid: 12560232
references.citation: Eur J Pharmacol. 2006 Mar 8;533(1-3):327-40
references.pmid: 16483568
references.citation: Blood. 2002 May 1;99(9):3342-9
references.pmid: 11964302
references.citation: Clin Exp Allergy. 2004 Jun;34(6):911-6
references.pmid: 15196279
references.citation: Blood. 2012 Sep 27;120(13):2669-78
references.pmid: 22806893
references.citation: Mol Cancer Res. 2012 Jul;10(7):881-91
references.pmid: 22589410
references.citation: Blood. 2007 May 1;109(9):3679-86
references.pmid: 17213284
references.citation: Biochim Biophys Acta. 2009 Aug;1796(1):19-26
references.pmid: 19233249
references.citation: Trends Immunol. 2011 Oct;32(10):478-85
references.pmid: 21917522
references.citation: Adv Exp Med Biol. 2011;716:270-88
references.pmid: 21713661
references.citation: Blood. 2001 Jul 15;98(2):343-50
references.pmid: 11435302
references.citation: Blood. 2011 May 19;117(20):5350-61
references.pmid: 21450902
references.citation: J Allergy Clin Immunol. 2000 Mar;105(3):455-61
references.pmid: 10719293
references.citation: Blood. 2011 Jul 28;118(4):1077-86
references.pmid: 21636860
references.citation: Mol Cell. 2004 Feb 13;13(3):341-55
references.pmid: 14967142
references.citation: EMBO J. 2000 May 2;19(9):2008-14
references.pmid: 10790367
references.citation: Adv Exp Med Biol. 2011;716:186-211
references.pmid: 21713658
references.citation: Curr Opin Genet Dev. 2006 Aug;16(4):339-47
references.pmid: 16806895
references.citation: Blood. 2011 Apr 21;117(16):4253-61
references.pmid: 21398220
references.citation: J Immunol. 2009 Oct 15;183(8):4940-7
references.pmid: 19786542
references.citation: Mol Cell Biol. 2004 Jun;24(12):5340-52
references.pmid: 15169898
references.citation: Physiol Rev. 2012 Oct;92(4):1619-49
references.pmid: 23073628
references.citation: Clin Exp Allergy. 2006 Mar;36(3):317-24
references.pmid: 16499642
references.citation: Mol Cell Biol. 2002 Sep;22(18):6363-74
references.pmid: 12192036
references.citation: J Biol Chem. 2006 Sep 29;281(39):28615-26
references.pmid: 16873377
references.citation: Cell Signal. 2012 Feb;24(2):353-362
references.pmid: 21893191
references.citation: Br J Cancer. 2006 Apr 24;94(8):1180-5
references.pmid: 16570044
references.citation: J Biol Chem. 1992 Sep 5;267(25):18021-5
references.pmid: 1381360
references.citation: Front Immunol. 2012 May 25;3:119
references.pmid: 22654878
references.citation: Blood. 2008 Aug 15;112(4):1269-79
references.pmid: 18524989
references.citation: Blood. 2008 Dec 1;112(12):4646-54
references.pmid: 18768391
references.citation: J Biol Chem. 2009 May 15;284(20):13481-13488
references.pmid: 19287004
references.citation: Am J Pathol. 1999 Apr;154(4):1259-65
references.pmid: 10233863
references.citation: J Med Chem. 2010 Mar 25;53(6):2482-93
references.pmid: 20170098