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Helicobacter pylori-induced changes in microtubule dynamics conferred by α-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin

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Abstract

Regulation of matrix metalloproteinase-9 (MMP-9) secretion in response to proinflammatory challenge remains under a strict control of factors that affect the stability dynamics of the major cytoskeleton polymeric structures, microtubules (MTs). In this study, we report that H. pylori LPS-elicited induction gastric mucosal MMP-9 secretion is accompanied by the enhancement in MT stabilization as evidenced by the increase in α-tubulin acetylation and detyrosination while the modulatory influence of hormone, ghrelin, is associated with MT destabilization and reflected in a decrease in α-tubulin acetylation and detyrosination. Further, we reveal that the LPS-induced enhancement in MT stabilization and up-regulation in MMP-9 secretion as well as the modulatory influence of ghrelin occur with the involvement of PKCδ and SFK. The LPS effect is reflected in a marked increase in PKCδ-mediated α-tubulin phosphorylation on Ser, while the modulatory effect of ghrelin on MT dynamics and MMP-9 secretion is manifested by the SFK-dependent phosphorylation of α-tubulin on Tyr. Moreover, the changes in α-tubulin phosphorylation and MT stabilization dynamics occur in concert with the Golgi recruitment and activation of PKD2 and Arf-GEF. The findings demonstrate that the enhancement in gastric mucosal MMP-9 secretion in response to H. pylori and its modulation by ghrelin are the result of changes in MT dynamics conferred by PKCδ/SFK- mediated α-tubulin Ser/Tyr phosphorylation.

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References

  • Bergin PJ, Edebo A, Wen S et al (2004) Increased production of matrix metalloproteinases in Helicobacter pylori-associated human gastritis. Helicobacter 9:201–210

    Article  CAS  PubMed  Google Scholar 

  • Bonnemaison ML, Eipper BA, Mains RE (2013) Role of adaptor proteins in secretory granule biogenesis and maturation. Frontiers Endocrinol 4:1–17. doi:10.3389/fendo.2013.00101. Art ID: 101

    Article  Google Scholar 

  • Bourgoin SG, El Azreq MA (2012) Small inhibitors of ADP-ribosylation factor activation and function in mammalian cells. World J Pharmacol 1:55–64

    Article  Google Scholar 

  • Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93:269–309

    Article  CAS  PubMed  Google Scholar 

  • De S, Tsimounis A, Chen X, Rotenberg SA (2014) Phosphorylation of α-tubulin by protein kinase C stimulates microtubule dynamics in human breast cells. Cytoskeleton 71:252–272

    Article  Google Scholar 

  • Donaldson JG, Jackson CL (2011) ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol 12:362–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eiseler T, Wille C, Koehler C, Illing A, Seufferlein T (2016) Protein kinase D2 assembles a multiprotein complex at the trans-Gologi network to regulate matrix metalloproteinase secretion. J Biol Chem 291:462–477

    Article  CAS  PubMed  Google Scholar 

  • Fourest-Lieuvin A, Peris L, Gache V et al (2006) Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Mol Biol Cell 17:1041–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goode BL, Durbin DG, Barnes G (2000) Functional cooperation between the microtubule and actin in cytoskeletons. Curr Opin Cell Biol 12:63–71

    Article  CAS  PubMed  Google Scholar 

  • Gu S, Liu Y, Zhu B et al (2016) Loss of α-tubulin acetylation is associated with TGF-β-induced epithelial-mesenchymal transition. J Biol Chem 291:5396–5405

    Article  CAS  PubMed  Google Scholar 

  • Hanania R, Sun HS, Xu K et al (2012) Classically activated macrophages use stable microtubules for matrix metalloproteinase-9 (MMP-9) secretion. J Biol Chem 287:8468–8483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howes SC, Alushin GM, Shida T, Nachury MV, Nogales E (2014) Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure. Mol Biol Cell 25:257–266

    Article  PubMed  PubMed Central  Google Scholar 

  • Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev 4:253–265

    Article  CAS  Google Scholar 

  • Kalebic N, Martinez C, Perlas M et al (2013) Tubulin acetyltransferase aTAT1 destabilizes microtubules independently of its acetylation activity. Mol Cell Biol 33:1114–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubben FJGM, Sier CFM, Schram M et al (2007) Eradication of Helicobacter pylori infection favourably affects altered gastric mucosal MMP-9 levels. Helicobacter 12:498–504

    Article  CAS  PubMed  Google Scholar 

  • Laurent CE, Delfino FJ, Cheng HY, Smithgall TE (2004) The human c-Fes tyrosine kinase binds tubulin and microtubules through separate domains and promotes microtubule assembly. Mol Cell Biol 24:9351–9358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma X, Sayeski PP (2007) Identification of tubulin as a substrate of Jak2 tyrosine kinase and its role in Jak2-dependent signaling. Biochemistry 46:7153–7162

    Article  CAS  PubMed  Google Scholar 

  • Nirschl JJ, Magiera MM, Lazarus JE, Janke C, Holzbaur ELF (2016) α-Tubulin tyrosination and CLIP-170 phosphorylation regulate the initiation of dynein- driven transport in neurons. Cell Rep 14:2637–2652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piotrowski J, Piotrowski E, Skrodzka D, Slomiany A, Slomiany BL (1997) Induction of acute gastritis and epithelial cell apoptosis by Helicobacter pylori lipopolysaccharide. Scand J Gastroenterol 32:203–211

    Article  CAS  PubMed  Google Scholar 

  • Rozengurt E (2011) Protein kinase D signaling: multiple biological functions in health and disease. Physiology 26:23–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sampieri CL (2013) Helicobacter pylori and gastritis: the role of extracellular matrix metalloproteases, their inhibitors, and the disintegrins and metalloproteases—a systematic literature review. Dig Dis Sci 58:2777–2783

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2013) Induction in gastric mucosal prostaglandin and nitric oxide by Helicobacter pylori is dependent on MAPK/ERK-mediated activation of IKK-β and cPLA2: modulatory effect of ghrelin. Inflammopharmacology 21:241–251

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2014) Modulation of gastric mucosal inflammatory responses to Helicobacter pylori via ghrelin-induced protein kinase Cδ tyrosine phosphorylation. Inflammopharmacology 22:251–262

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2015) Regulatory role of guanine nucleotide exchange factor (GEF) Dock180 phosphorylation on Tyr/Ser in mediation of gastric mucosal Rac1 activation in response to Helicobacter pylori and ghrelin. Inflammopharmacology 23:111–118

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2016a) Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation. Inflammopharmacology 24:23–31

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2016b) Helicobacter pylori-elicited induction in gastric mucosal matrix metalloproteinase-9 (MMP-9) release involves ERK- dependent cPLA2 activation and its recruitment to the membrane-localized Rac1/p38 complex. Inflammopharmacology 24:87–95

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2016c) Role of protein kinase D2 phosphorylation on Tyr in modulation of by ghrelin of Helicobacter pylori-induced up-regulation in gastric mucosal matrix metalloproteinase-9 (MMP-9) secretion. Inflammopharmacology 24:119–126

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2016d) Role of α-tubulin acetylation and protein kinase D2 Ser/Tyr phosphorylation in modulation by ghrelin of Porphyromonas gingivalis-induced enhancement in MMP-9 secretion by salivary gland cells. J Biosci Med 4:82–94

    Google Scholar 

  • Slomiany A, Grabska M, Slomiany BA, Grzelinska E, Morita M, Slomiany BL (1993) Intracellular transport, organelle biogenesis and establishment of Golgi identity: impact of Brefeldin A on the activity of lipid-synthesizing enzymes. Int J Biochem 25:891–901

    Article  CAS  PubMed  Google Scholar 

  • Vandooren J, Van den Steen PE, Opdenakker G (2013) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol 48:222–272

    Article  CAS  PubMed  Google Scholar 

  • Wille C, Kohler C, Armacki M et al (2014) Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases. Mol Biol Cell 25:324–336

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Gaillard S, Phillip JM, Huang TC et al (2015) Inhibition of spleen tyrosine kinase potentiates paclitaxel-induced cytotoxicity in ovarian cancer cells by stabilizing microtubules. Cancer Cell 28:82–96

    Article  CAS  PubMed  Google Scholar 

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  1. Research Center, C875 Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103–2400, USA

    B. L. Slomiany & A. Slomiany

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  1. B. L. Slomiany
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  2. A. Slomiany
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Correspondence to B. L. Slomiany.

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Slomiany, B.L., Slomiany, A. Helicobacter pylori-induced changes in microtubule dynamics conferred by α-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin. Inflammopharmacol 24, 197–205 (2016). https://doi.org/10.1007/s10787-016-0278-z

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  • DOI: https://doi.org/10.1007/s10787-016-0278-z

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