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We show for the first time expression of ATP6V1B1 in submandibular gland and introduce transforming growth factor\u2010beta (TGF\u2010\u03b2) as a novel regulator of V\u2010ATPase subunits. Using QRT\u2010PCR, immunoblotting, biotinylation of surface proteins, immunofluorescence, chromatin immunoprecipitation, and intracellular H(<jats:sup>+<\/jats:sup>) recording with H(<jats:sup>+<\/jats:sup>)\u2010sensitive dye 2\u2032,7\u2032\u2010bis\u2010(carboxyethyl)\u20105\u2010(and\u20106)\u2010carboxyfluorescein we show that in the human submandibular gland (HSG) cell line, activation of TGF\u2010\u03b2 signaling upregulates ATP6V1E1 and ATP6V1B2, downregulates ATP6V1B1, and has no effect on ATP6V1A. TGF\u2010\u03b21 effects on ATP6V1B1 are mediated through the canonical, the soluble adenylate cyclase, and ERK signaling. A CREB binding sequence was identified in the ATP6V1B1 promoter and CREB binding decreased after TGF\u2010\u03b21 treatment. Following acidosis, a bafilomycin\u2010sensitive and Na<jats:sup>+<\/jats:sup>\u2010independent cell pH recovery was observed in HSG cells, an effect that was not influenced after disruption of acidic lysosomes. Moreover, neutralization of TGF\u2010\u03b2s, inhibition of TGF\u2010\u03b2 receptor, or inhibition of the canonical pathway decreased membrane expression of ATP6V1A and prevented the acidosis\u2010induced increased V\u2010ATPase activity. The results suggest multiple modes of action of TGF\u2010\u03b21 on V\u2010ATPase subunits in HSG cells: TGF\u2010\u03b21 may regulate transcription or protein synthesis of certain subunits and trafficking of other subunits in a context\u2010dependent manner. Moreover, surface V\u2010ATPase is active in salivary duct cells and involved in intracellular pH regulation following acidosis.<\/jats:p>","DOI":"10.1002\/jcp.28147","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T06:19:35Z","timestamp":1547619575000},"page":"15061-15079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Differential regulation of vacuolar H<sup>+<\/sup>\u2010ATPase subunits by transforming growth factor\u2010\u03b21 in salivary ducts"],"prefix":"10.1002","volume":"234","author":[{"given":"Milena","family":"Kluge","sequence":"first","affiliation":[{"name":"Department of Molecular Embryology Faculty of Medicine, Institute of Anatomy and Cell Biology, University of Freiburg Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun","family":"Namkoong","sequence":"additional","affiliation":[{"name":"Department of Physiology School of Dentistry, Seoul National University Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shokoufeh","family":"Khakipoor","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology Faculty of Medicine, Institute of Anatomy and Cell Biology, University of Freiburg Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyungpyo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology School of Dentistry, Seoul National University Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-1597","authenticated-orcid":false,"given":"Eleni","family":"Roussa","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology Faculty of Medicine, Institute of Anatomy and Cell Biology, University of Freiburg Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,1,15]]},"reference":[{"key":"e_1_2_7_1_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3810"},{"key":"e_1_2_7_1_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00362.2013"},{"key":"e_1_2_7_1_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00303.2013"},{"key":"e_1_2_7_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840220524"},{"key":"e_1_2_7_1_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00007.2013"},{"key":"e_1_2_7_1_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00278.2011"},{"key":"e_1_2_7_1_8_1","first-page":"11126","article-title":"Transforming growth factor\u2010b1 decreases epithelial sodium channel functionality in renal collecting duct cells via Smad4\u2010dependent pathway","volume":"23","author":"Chang C. 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