title: MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells.
abstract: Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-alpha (TGF-alpha), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-alpha (TNF-alpha)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-alpha increases MSC-derived hepatocyte growth factor (HGF) production. TGF-alpha-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-alpha and TNF-alpha was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-alpha/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-alpha stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-alpha and TNF-alpha-stimulated HGF.
authors.affiliation: Departments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Brent R
authors.initials: BR
authors.lastname: Weil
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Abarbanell
authors.forename: Jiangning
authors.initials: J
authors.lastname: Tan
authors.forename: Troy A
authors.initials: TA
authors.lastname: Markel
authors.forename: Megan L
authors.initials: ML
authors.lastname: Kelly
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering; D020239:Receptor Cross-Talk / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases
references.citation: Prog Growth Factor Res. 1991;3(1):67-85
references.pmid: 1838014
references.citation: J Biol Chem. 1998 Oct 23;273(43):28155-62
references.pmid: 9774435
references.citation: Circ Res. 2005 Feb 18;96(3):300-7
references.pmid: 15637298
references.citation: Cell. 1987 Sep 25;50(7):1131-7
references.pmid: 3497724
references.citation: Mol Ther. 2003 Sep;8(3):467-74
references.pmid: 12946320
references.citation: Clin Exp Immunol. 2007 Aug;149(2):353-63
references.pmid: 17521318
references.citation: Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2308-14
references.pmid: 18849336
references.citation: Biochem Biophys Res Commun. 2001 Feb 23;281(2):373-7
references.pmid: 11181057
references.citation: Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):69-75
references.pmid: 12524227
references.citation: Mol Ther. 2008 Jun;16(6):1129-37
references.pmid: 18431364
references.citation: J Mol Cell Cardiol. 2005 Aug;39(2):363-76
references.pmid: 15992820
references.citation: Biochem J. 2000 Aug 1;349 Pt 3:869-76
references.pmid: 10903150
references.citation: Stem Cells. 2004;22(3):405-14
references.pmid: 15153617
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Circulation. 2006 Jul 4;114(1 Suppl):I282-9
references.pmid: 16820587
references.citation: Am J Physiol Cell Physiol. 2008 Mar;294(3):C675-82
references.pmid: 18234850
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G657-62
references.pmid: 17640973
references.citation: J Biol Chem. 2004 Jul 30;279(31):32869-81
references.pmid: 15155767
references.citation: Biol Reprod. 2007 Apr;76(4):611-8
references.pmid: 17182889
references.citation: J Clin Invest. 2001 Jun;107(11):1355-6
references.pmid: 11390416
references.citation: J Biol Chem. 2005 Oct 28;280(43):36099-109
references.pmid: 16141211
references.citation: Gastroenterology. 1995 Jul;109(1):24-31
references.pmid: 7797021
references.citation: Cell. 1988 Aug 26;54(5):593-5
references.pmid: 3044605
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):655-62
references.pmid: 18545270
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1115-23
references.pmid: 18685072
references.citation: Eur J Surg. 1991 Oct;157(10):607-11
references.pmid: 1687253
references.citation: Circ Res. 2006 Aug 18;99(4):434-41
references.pmid: 16857964
references.citation: BMC Neurosci. 2006 Jun 22;7:51
references.pmid: 16792806
references.citation: Science. 1988 Aug 5;241(4866):708-12
references.pmid: 3041594
references.citation: J Cell Biochem. 1991 Apr;45(4):346-52
references.pmid: 2045428
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2557-67
references.pmid: 15897328
references.citation: Am J Physiol Renal Physiol. 2005 Jul;289(1):F31-42
references.pmid: 15713913
references.citation: FASEB J. 2006 Apr;20(6):661-9
references.pmid: 16581974
references.citation: FASEB J. 2006 Aug;20(10):1589-98
references.pmid: 16873882
references.citation: Biochem J. 2000 Oct 1;351(Pt 1):95-105
references.pmid: 10998351
references.citation: Exp Cell Res. 2005 Oct 15;310(1):218-28
references.pmid: 16120441
references.citation: J Biol Chem. 1996 Mar 8;271(10):5871-7
references.pmid: 8621459
references.citation: Genes Dev. 1991 May;5(5):714-27
references.pmid: 1709129
references.citation: Gastroenterology. 1992 May;102(5):1467-74
references.pmid: 1568557
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: Shock. 2006 May;25(5):454-9
references.pmid: 16680009
references.citation: Endocrinology. 2008 Jun;149(6):2840-52
references.pmid: 18292192
references.citation: Exp Cell Res. 2005 Mar 10;304(1):305-16
references.pmid: 15707595
references.citation: Cancer Res. 2006 Apr 1;66(7):3802-12
references.pmid: 16585207
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L718-29
references.pmid: 15090366
references.citation: J Mol Cell Cardiol. 2003 Sep;35(9):1113-9
references.pmid: 12967634
references.citation: In Vitro Cell Dev Biol. 1988 Feb;24(2):149-54
references.pmid: 3277938
references.citation: Circulation. 2004 Apr 20;109(15):1892-7
references.pmid: 15051641
references.citation: J Neurosci. 2006 Sep 20;26(38):9703-12
references.pmid: 16988041
references.citation: J Biol Chem. 2005 Apr 29;280(17):17435-48
references.pmid: 15722553
references.citation: J Biol Chem. 1993 Aug 25;268(24):18213-7
references.pmid: 7688742