{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:58:17Z","timestamp":1793105897231,"version":"4.5.0"},"reference-count":63,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T00:00:00Z","timestamp":1507507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["519211"],"award-info":[{"award-number":["519211"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Latent transforming growth factor-\u03b2-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-\u03b21 (TGF-\u03b21) but appears to be implicated in the regulation of TGF-\u03b21 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-\u03b21 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-\u03b21 levels in the medium. However, the TGF-\u03b21 increase was due to an upregulation of TGF-\u03b21 expression and secretion rather than a displacement of matrix-stored TGF-\u03b21. The secreted TGF-\u03b21 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-\u03b2 expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-\u03b21 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins \u03b21 and \u03b1V\u03b25 showed no reduction of LTBP-2 stimulation of TGF-\u03b21. However, TGF-\u03b21 upregulation was partially inhibited by anti-\u03b1V\u03b23 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-\u03b21 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-\u03b21 signalling.<\/jats:p>","DOI":"10.3390\/ijms18102114","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T11:25:35Z","timestamp":1507548335000},"page":"2114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-\u03b21 in Fibroblasts via Akt and p38 Signalling Pathways"],"prefix":"10.3390","volume":"18","author":[{"given":"Mohamed","family":"Sideek","sequence":"first","affiliation":[{"name":"Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Department of Physical Rehabilitation Sciences, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Smith","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementine","family":"Menz","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Adams","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2885-2080","authenticated-orcid":false,"given":"Allison","family":"Cowin","sequence":"additional","affiliation":[{"name":"Regenerative Medicine, Future Industries Institute, University of South Australia, Adelaide, SA 5095, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gibson","sequence":"additional","affiliation":[{"name":"Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1242\/jcs.00229","article-title":"Making sense of latent TGF-\u03b2 activation","volume":"116","author":"Annes","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S1357-2725(97)00128-3","article-title":"Transforming growth factor-\u03b2 (TGF-\u03b2)","volume":"30","author":"Clark","year":"1998","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1513\/pats.201201-003AW","article-title":"TGF-\u03b2 activation and lung fibrosis","volume":"9","author":"Tatler","year":"2012","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4331\/wjbc.v3.i3.41","article-title":"Transforming growth factor-\u03b2 and smooth muscle differentiation","volume":"3","author":"Guo","year":"2012","journal-title":"World J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.bbadis.2009.06.004","article-title":"TGF-\u03b2 and fibrosis in different organs\u2014Molecular pathway imprints","volume":"1792","author":"Pohlers","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1042\/BST0370849","article-title":"Role of integrin-mediated TGF-\u03b2 activation in the pathogenesis of pulmonary fibrosis","volume":"37","author":"Goodwin","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/ng1001-117","article-title":"TGF-\u03b2 signaling in tumor suppression and cancer progression","volume":"29","author":"Derynck","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1038\/ki.1997.185","article-title":"Biology of TGF-\u03b2 in knockout and transgenic mouse models","volume":"51","author":"Bottinger","year":"1997","journal-title":"Kidney Int."},{"key":"ref_9","first-page":"81","article-title":"Latent forms of TGF-\u03b2: Molecular structure and mechanisms of activation","volume":"157","author":"Miyazono","year":"1991","journal-title":"Ciba Found. Symp."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7409","DOI":"10.1074\/jbc.R400029200","article-title":"Latent transforming growth factor-\u03b2 (TGF-\u03b2) binding proteins: Orchestrators of TGF-\u03b2 availability","volume":"280","author":"Rifkin","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0008-6363(01)00512-0","article-title":"Expression of latent TGF-\u03b2 binding proteins and association with TGF-\u03b2 1 and fibrillin-1 following arterial injury","volume":"53","author":"Sinha","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1091\/mbc.11.8.2691","article-title":"Specific sequence motif of 8-Cys repeats of TGF-\u03b2 binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-\u03b2","volume":"11","author":"Saharinen","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6932","DOI":"10.1128\/MCB.15.12.6932","article-title":"Bovine latent transforming growth factor \u03b2 1-binding protein 2: Molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils","volume":"15","author":"Gibson","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.matbio.2006.12.006","article-title":"LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein","volume":"26","author":"Hirani","year":"2007","journal-title":"Matrix Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32469","DOI":"10.1016\/S0021-9258(18)31659-4","article-title":"Identification and characterization of LTBP-2, a novel latent transforming growth factor-\u03b2-binding protein","volume":"269","author":"Moren","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1128\/MCB.20.13.4879-4887.2000","article-title":"Developmental expression of latent transforming growth factor \u03b2 binding protein 2 and its requirement early in mouse development","volume":"20","author":"Shipley","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5672","DOI":"10.1093\/hmg\/ddu283","article-title":"Latent TGF-\u03b2 binding protein-2 is essential for the development of ciliary zonule microfibrils","volume":"23","author":"Inoue","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/ejhg.2010.11","article-title":"LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma","volume":"18","author":"Desir","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ajhg.2009.03.017","article-title":"Null mutations in LTBP2 cause primary congenital glaucoma","volume":"84","author":"Ali","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/humu.22105","article-title":"LTBP2 mutations cause weill-marchesani and weill-marchesani-like syndrome and affect disruptions in the extracellular matrix","volume":"33","author":"Paylakhi","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cain, S.A., McGovern, A., Baldwin, A.K., Baldock, C., and Kielty, C.M. (2012). Fibrillin-1 mutations causing weill-marchesani syndrome and acromicric and geleophysic dysplasias disrupt heparan sulfate interactions. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048634"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1359\/jbmr.2000.15.1.68","article-title":"Role of the latent transforming growth factor \u03b2 binding protein 1 in fibrillin-containing microfibrils in bone cells in vitro and in vivo","volume":"15","author":"Dallas","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1242\/jcs.073437","article-title":"Assembly of fibrillin microfibrils governs extracellular deposition of latent TGF-\u03b2","volume":"123","author":"Chiu","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/(SICI)1098-1136(19990215)25:4<332::AID-GLIA3>3.0.CO;2-1","article-title":"TGF-\u03b21-dependent differential expression of a rat homolog for latent TGF-\u03b2 Binding protein in astrocytes and C6 glioma cells","volume":"25","author":"Krohn","year":"1999","journal-title":"Glia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S1357-2725(99)00120-X","article-title":"Characterisation of fibrillin-1 cDNA clones in a human fibroblast cell line that assembles microfibrils","volume":"32","author":"Kettle","year":"2000","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1242\/jcs.106.1.167","article-title":"Synthesis and assembly of fibrillin by fibroblasts and smooth muscle cells","volume":"106","author":"Kielty","year":"1993","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/0006-291X(69)90351-9","article-title":"The mechanism of cycloheximide inhibition of protein synthesis in rabbit reticulocytes","volume":"36","author":"McKeehan","year":"1969","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24705","DOI":"10.1074\/jbc.M212953200","article-title":"Latent transforming growth factor-\u03b2-binding protein 2 is an adhesion protein for melanoma cells","volume":"278","author":"Vehvilainen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Menz, C., Parsi, M.K., Adams, J.R., Sideek, M.A., Kopecki, Z., Cowin, A.J., and Gibson, M.A. (2015). LTBP-2 has a single high-affinity binding site for FGF-2 and blocks FGF-2-induced cell proliferation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135577"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.matbio.2010.03.005","article-title":"LTBP-2 has multiple heparin\/heparan sulfate binding sites","volume":"29","author":"Parsi","year":"2010","journal-title":"Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/art.24485","article-title":"Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies","volume":"60","author":"Damjanov","year":"2009","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1083\/jcb.200608167","article-title":"Fibrillin-1 regulates the bioavailability of TGF-\u03b21","volume":"176","author":"Chaudhry","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/jcp.21278","article-title":"The integrin-growth factor receptor duet","volume":"213","author":"Alam","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S0959-437X(00)00155-6","article-title":"Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression","volume":"11","author":"Assoian","year":"2001","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1530\/JOE-10-0377","article-title":"Extracellular matrix and cell signalling: The dynamic cooperation of integrin, proteoglycan and growth factor receptor","volume":"209","author":"Kim","year":"2011","journal-title":"J. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1016\/j.biomaterials.2013.01.092","article-title":"The antagonistic roles of PDGF and integrin \u03b1v\u03b23 in regulating ROS production at focal adhesions","volume":"34","author":"Lin","year":"2013","journal-title":"Biomaterials"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/S0955-0674(00)00254-4","article-title":"Syndecan-4 and focal adhesion function","volume":"13","author":"Woods","year":"2001","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1042\/BJ20100323","article-title":"Mechanisms and functions of p38 MAPK signalling","volume":"429","author":"Cuadrado","year":"2010","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1128\/MMBR.68.2.320-344.2004","article-title":"ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions","volume":"68","author":"Roux","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16415","DOI":"10.1074\/jbc.273.26.16415","article-title":"Induction of apoptosis by SB202190 through inhibition of p38\u03b2 mitogen-activated protein kinase","volume":"273","author":"Nemoto","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/ard.2007.074278","article-title":"The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis","volume":"67","author":"Schett","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/74680","article-title":"Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway","volume":"6","author":"Otterbein","year":"2000","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1582-4934.2005.tb00337.x","article-title":"The activation of Akt\/PKB signaling pathway and cell survival","volume":"9","author":"Song","year":"2005","journal-title":"J. Cell. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ctrv.2003.07.007","article-title":"PI3K\/Akt signalling pathway and cancer","volume":"30","author":"Casado","year":"2004","journal-title":"Cancer Treat. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/ndt\/gfu196","article-title":"Potential role of Akt signaling in chronic kidney disease","volume":"30","author":"Lan","year":"2015","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1055\/s-0032-1333284","article-title":"The fibrotic role of phosphatidylinositol-3-kinase\/Akt pathway in injured skeletal muscle after acute contusion","volume":"34","author":"Li","year":"2013","journal-title":"Int. J. Sports Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36204","DOI":"10.1074\/jbc.M114.593285","article-title":"Modulation of the mevalonate pathway by Akt regulates macrophage survival and development of pulmonary fibrosis","volume":"289","author":"Murthy","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7455","DOI":"10.1038\/sj.onc.1209085","article-title":"Perturbations of the Akt signaling pathway in human cancer","volume":"24","author":"Altomare","year":"2005","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.bbrc.2015.11.099","article-title":"miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1","volume":"469","author":"Zhang","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1093\/ajh\/hpt123","article-title":"Role of Akt1 in cardiac fibrosis induced by angiotensin II","volume":"26","author":"Miao","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cyto.2011.01.005","article-title":"Blockade of the Ras\/MEK\/ERK and Ras\/PI3K\/Akt pathways by statins reduces the expression of BFGF, HGF, and TGF-\u03b2 as angiogenic factors in mouse osteosarcoma","volume":"54","author":"Tsubaki","year":"2011","journal-title":"Cytokine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.febslet.2006.12.032","article-title":"Involvement of phosphatidylinositol-3-kinase and ERK pathways in the production of TGF-\u03b21 by macrophages treated with liposomes composed of phosphatidylserine","volume":"581","author":"Otsuka","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.4049\/jimmunol.181.5.3575","article-title":"Transcriptional and translational regulation of transforming growth factor-\u03b2 production in response to apoptotic cells","volume":"181","author":"Xiao","year":"2008","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"503","DOI":"10.3727\/096504016X14755368915591","article-title":"Knockdown of latent transforming growth factor-\u03b2 (TGF-\u03b2)-binding protein 2 (LTBP2) inhibits invasion and tumorigenesis in thyroid carcinoma cells","volume":"25","author":"Wan","year":"2017","journal-title":"Oncol. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"453801","DOI":"10.1155\/2015\/453801","article-title":"Heparan sulfate proteoglycans may promote or inhibit cancer progression by interacting with integrins and affecting cell migration","volume":"2015","author":"Soares","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.cellsig.2011.05.004","article-title":"Akt signalling in health and disease","volume":"23","author":"Hers","year":"2011","journal-title":"Cell Signal."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.tcm.2005.11.003","article-title":"Platelet-derived growth factor-BB transactivates the fibroblast growth factor receptor to induce proliferation in human smooth muscle cells","volume":"16","author":"Millette","year":"2006","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14824","DOI":"10.1074\/jbc.M113.451336","article-title":"Transforming growth factor-\u03b21 (TGF-\u03b21)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts","volume":"288","author":"Midgley","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"MacFarlane, E.G., Haupt, J., Dietz, H.C., and Shore, E.M. (2017). TGF-\u03b2 family signaling in connective tissue and skeletal diseases. Cold Spring Harb. Perspect. Biol.","DOI":"10.1101\/cshperspect.a022269"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Wee, P., and Wang, Z. (2017). Epidermal growth factor receptor cell proliferation signaling pathways. Cancers, 9.","DOI":"10.3390\/cancers9050052"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and smad-independent pathways in TGF-\u03b2 family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/wound.2012.0406","article-title":"Critical role of transforming growth factor \u03b2 in different phases of wound healing","volume":"2","author":"Pakyari","year":"2013","journal-title":"Adv. Wound Care"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10735-015-9645-0","article-title":"Co-localization of LTBP-2 with FGF-2 in fibrotic human keloid and hypertrophic scar","volume":"47","author":"Sideek","year":"2016","journal-title":"J. Mol. Histol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:46:48Z","timestamp":1760208408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,9]]},"references-count":63,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["ijms18102114"],"URL":"https:\/\/doi.org\/10.3390\/ijms18102114","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,9]]}}}