{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPINT2, also known as hepatocyte growth factor activator inhibitor type‐2 (HAI‐2), is a Kunitz‐type serine protease inhibitor that plays a critical role in regulating pericellular proteolysis. By inhibiting key activators such as the hepatocyte growth factor activator (HGFA) and membrane‐bound proteases including matriptase and prostasin, SPINT2 modulates the HGF/MET signaling cascade and thereby influences cell–cell interactions, migration, and invasion. This precise proteolytic control is essential for maintaining normal tissue homeostasis and preventing aberrant protease activities that may otherwise trigger pathological processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMultiple studies have identified SPINT2 as a tumor suppressor whose loss or inactivation—commonly through promoter hypermethylation or deleterious mutations—leads to the deregulation of pivotal proteolytic networks. In various malignancies, including renal cell carcinoma, medulloblastoma, hepatocellular carcinoma, esophageal squamous cell carcinoma, and prostate and ovarian cancers, decreased SPINT2 expression is associated with enhanced protease activity, increased tumor cell motility, invasion, and metastatic potential. Restoration of SPINT2 expression, whether by genetic re-expression or pharmacological demethylation, is shown to curb these aggressive cellular behaviors by reining in the HGF/MET pathway and its downstream signaling cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "32"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its tumor‐suppressive functions, SPINT2 is also implicated in congenital disorders and the regulation of developmental and physiological processes. Mutations in SPINT2 are causative of syndromic forms of congenital sodium diarrhea and congenital tufting enteropathy, conditions marked by disrupted epithelial barrier function and unrestrained protease activity. Moreover, SPINT2 contributes to the proper functioning of diverse tissues such as the placenta and testis, and modulates extracellular protease–inhibitor interactions within the tumor microenvironment. Epigenetic regulation of SPINT2, alongside its potential restoration by demethylating agents, underscores its promise as a therapeutic target across a spectrum of pathophysiological states."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "44"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christian Parr, Gareth Watkins, Robert E Mansel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hepatocyte growth factor regulatory factors in human breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.ccr-0553-3"}], "href": "https://doi.org/10.1158/1078-0432.ccr-0553-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14734471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14734471"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "H Kataoka, T Shimomura, T Kawaguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M006412200"}], "href": "https://doi.org/10.1074/jbc.M006412200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11013244"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11013244"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mark R Morris, Dean Gentle, Mahera Abdulrahman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-04-3371"}], "href": "https://doi.org/10.1158/0008-5472.CAN-04-3371"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15930277"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15930277"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Roman Szabo, John P Hobson, Karin List, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potent inhibition and global co-localization implicate the transmembrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M801970200"}], "href": "https://doi.org/10.1074/jbc.M801970200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18713750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18713750"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Peter Heinz-Erian, Thomas Müller, Birgit Krabichler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2009.01.004"}], "href": "https://doi.org/10.1016/j.ajhg.2009.01.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19185281"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19185281"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Paul N Kongkham, Paul A Northcott, Young Shin Ra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-08-2169"}], "href": "https://doi.org/10.1158/0008-5472.CAN-08-2169"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19047176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19047176"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Julie Salomon, Olivier Goulet, Danielle Canioni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-013-1380-6"}], "href": "https://doi.org/10.1007/s00439-013-1380-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24142340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24142340"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mika Suzuki, Hiroshi Kobayashi, Yoshiko Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.10950"}], "href": "https://doi.org/10.1002/ijc.10950"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12569552"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12569552"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kenichi Fukai, Osamu Yokosuka, Tetsuhiro Chiba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene is frequently hypermethylated in human hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14695180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14695180"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "C-H Tsai, C-H Teng, Y-T Tu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2013.412"}], "href": "https://doi.org/10.1038/onc.2013.412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24121274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24121274"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Mika Suzuki, Hiroshi Kobayashi, Yoshiko Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bikunin target genes in ovarian cancer cells identified by microarray analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M300239200"}], "href": "https://doi.org/10.1074/jbc.M300239200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12571229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12571229"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Wenjie Dong, Xiaobing Chen, Jing Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic inactivation and tumor suppressor activity of HAI-2/SPINT2 in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.25161"}], "href": "https://doi.org/10.1002/ijc.25161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20063316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20063316"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Keiichiro Nakamura, Atsushi Hongo, Junichi Kodama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in endometrial cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.25606"}], "href": "https://doi.org/10.1002/ijc.25606"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20715109"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20715109"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Hang Su, Jing Zhao, Yujuan Xiong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mutat Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mrfmmm.2008.02.005"}], "href": "https://doi.org/10.1016/j.mrfmmm.2008.02.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18358501"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18358501"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Hiroshi Kobayashi, Mika Suzuki, Naohiro Kanayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of urokinase receptor expression by bikunin is associated with inhibition of upstream targets of extracellular signal-regulated kinase-dependent cascade."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Biochem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1432-1033.2002.03068.x"}], "href": "https://doi.org/10.1046/j.1432-1033.2002.03068.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12180971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12180971"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Kiyoshi Wakahara, Hiroshi Kobayashi, Tatsuo Yagyu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bikunin suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor- alpha and interleukin-1 beta in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Infect Dis (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/428134"}], "href": "https://doi.org/10.1086/428134"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15717269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15717269"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Keiichiro Nakamura, Fernando Abarzua, Junichi Kodama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19148468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19148468"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Christopher Bergum, Karin List "}, {"type": "b", "children": [{"type": "t", "text": "Loss of the matriptase inhibitor HAI-2 during prostate cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostate (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pros.21177"}], "href": "https://doi.org/10.1002/pros.21177"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20687215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20687215"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Charlotte Mizon, Frank Piva, Viviane Queyrel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urinary bikunin determination provides insight into proteinase/proteinase inhibitor imbalance in patients with inflammatory diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Chem Lab Med (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1515/CCLM.2002.100"}], "href": "https://doi.org/10.1515/CCLM.2002.100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12211652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12211652"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Mika Suzuki, Hiroshi Kobayashi, Michio Fujie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kunitz-type protease inhibitor bikunin disrupts phorbol ester-induced oligomerization of CD44 variant isoforms containing epitope v9 and subsequently suppresses expression of urokinase-type plasminogen activator in human chondrosarcoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M108545200"}], "href": "https://doi.org/10.1074/jbc.M108545200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11777908"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11777908"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Soonyean Hwang, Hye-Eun Kim, Michelle Min, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2015.160"}], "href": "https://doi.org/10.1038/jid.2015.160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25910030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25910030"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Dongli Yue, Qingxia Fan, Xinfeng Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic inactivation of SPINT2 is associated with tumor suppressive function in esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2013.11.009"}], "href": "https://doi.org/10.1016/j.yexcr.2013.11.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24269829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24269829"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Matthew B Seefeldt, Jun Ouyang, Wayne A Froland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-pressure refolding of bikunin: efficacy and thermodynamics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1110/ps.04891204"}], "href": "https://doi.org/10.1110/ps.04891204"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15388859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15388859"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Eva Maurer, Michael Gütschow, Marit Stirnberg "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20121518"}], "href": "https://doi.org/10.1042/BJ20121518"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23293962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23293962"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Nicolas Faller, Ivan Gautschi, Laurent Schild "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of a missense mutation in the serine protease inhibitor SPINT2 associated with congenital sodium diarrhea."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0094267"}], "href": "https://doi.org/10.1371/journal.pone.0094267"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24722141"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24722141"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Edmund Kwok-Kwan Tung, Chun-Ming Wong, Tai-On Yau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.24115"}], "href": "https://doi.org/10.1002/ijc.24115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19107935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19107935"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Lasse Holt-Danborg, Julia Vodopiutz, Annika W Nonboe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy394"}], "href": "https://doi.org/10.1093/hmg/ddy394"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30445423"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30445423"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Andrew S Murray, Fausto A Varela, Thomas E Hyland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.775999"}], "href": "https://doi.org/10.1074/jbc.M117.775999"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28710277"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28710277"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "K Nakamura, F Abarzua, A Hongo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte growth factor activator inhibitor-2 (HAI-2) is a favorable prognosis marker and inhibits cell growth through the apoptotic pathway in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdn556"}], "href": "https://doi.org/10.1093/annonc/mdn556"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18689863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18689863"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Annika W Nonboe, Oliver Krigslund, Christoffer Soendergaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/tra.12482"}], "href": "https://doi.org/10.1111/tra.12482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28371047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28371047"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Hsiang-Hua D Chang, Yuan Xu, Hongyu Lai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0120489"}], "href": "https://doi.org/10.1371/journal.pone.0120489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25786220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25786220"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Shiao-Pieng Lee, Chen-Yu Kao, Shun-Cheng Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue distribution and subcellular localizations determine in vivo functional relationship among prostasin, matriptase, HAI-1, and HAI-2 in human skin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0192632"}], "href": "https://doi.org/10.1371/journal.pone.0192632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29438412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29438412"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Marco R Straus, Jonathan T Kinder, Michal Segall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Virology (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.virol.2020.01.004"}], "href": "https://doi.org/10.1016/j.virol.2020.01.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32056846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32056846"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Masamichi Yamauchi, Hiroshi Itoh, Seiji Naganuma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in human testis: identification of a distinct transcription start site for the HAI-2 gene in testis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1515/BC.2002.220"}], "href": "https://doi.org/10.1515/BC.2002.220"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12553733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12553733"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Osamu Nagakawa, Toshiya Yamagishi, Takuya Akashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum hepatocyte growth factor activator inhibitor type I (HAI-I) and type 2 (HAI-2) in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostate (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pros.20301"}], "href": "https://doi.org/10.1002/pros.20301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16353247"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16353247"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Shang-Ru Wu, Chen-Hsin Teng, Ya-Ting Tu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-15415-4"}], "href": "https://doi.org/10.1038/s41598-017-15415-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29118397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29118397"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Maria d'Apolito, Daniela Pisanelli, Flavio Faletra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic analysis of Italian patients with congenital tufting enteropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Pediatr (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12519-015-0070-y"}], "href": "https://doi.org/10.1007/s12519-015-0070-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26684320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26684320"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Fernanda Marconi Roversi, Nathalia Moreno Cury, Matheus Rodrigues Lopes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.14066"}], "href": "https://doi.org/10.1111/jcmm.14066"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30484958"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30484958"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Shang-Ru Wu, Chia-Hao Lin, Han-Po Shih, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41416-019-0400-2"}], "href": "https://doi.org/10.1038/s41416-019-0400-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30765871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30765871"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Kristin E Hirabayashi, Anthony T Moore, Bryce A Mendelsohn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.38637"}], "href": "https://doi.org/10.1002/ajmg.a.38637"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29575628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29575628"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Sara Vanessa Bernhard, Katarzyna Seget-Trzensiok, Christian Kuffer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of USP28 and SPINT2 expression promotes cancer cell survival after whole genome doubling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Oncol (Dordr) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13402-021-00654-5"}], "href": "https://doi.org/10.1007/s13402-021-00654-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34962618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34962618"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Márcia Santos Pereira, Sónia Pires Celeiro, Ângela Margarida Costa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of SPINT2 expression frequently occurs in glioma, leading to increased growth and invasion via MMP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Oncol (Dordr) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13402-019-00475-7"}], "href": "https://doi.org/10.1007/s13402-019-00475-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31701492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31701492"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Márcia Santos Pereira, Gisele Caravina de Almeida, Filipe Pinto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SPINT2 Deregulation in Prostate Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Histochem Cytochem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1369/0022155415612874"}], "href": "https://doi.org/10.1369/0022155415612874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26442953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26442953"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "Ciara N Murphy, Susan P Walker, Teresa M MacDonald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22147467"}], "href": "https://doi.org/10.3390/ijms22147467"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34299087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34299087"}]}]}]}