{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:28:09Z","timestamp":1791120489203,"version":"4.1.0"},"reference-count":22,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":488,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"NIH","award":["R01CA095782"],"award-info":[{"award-number":["R01CA095782"]}]},{"name":"NIH","award":["R01AA018713 awarded"],"award-info":[{"award-number":["R01AA018713 awarded"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Met, the transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF), is known to function as a potent antiapoptotic mediator in normal and neoplastic cells. Herein we report that the intracellular cytoplasmic tail of Met has evolved to harbor a tandem pair of caspase-3 cleavage sites, which bait, trap, and disable the active site of caspase-3, thereby blocking the execution of apoptosis. We call this caspase-3 cleavage motif the Death Defying Domain (DDD). This site consists of the following sequence: DNAD-DEVD-T (where the hyphens denote caspase cleavage sites). Through functional and mechanistic studies, we show that upon DDD cleavage by caspase-3 the resulting DEVD-T peptide acts as a competitive inhibitor and entraps the active site of caspase-3 akin to DEVD-CHO, which is a potent, synthetic inhibitor of caspase-3 activity. By gain- and loss-of-function studies using restoration of DDD expression in DDD-deficient hepatocytic cells, we found that both caspase-3 sites in DDD are necessary for inhibition of caspase-3 and promotion of cell survival. Employing mutagenesis studies, we show that DDD could operate independently of Met's enzymatic activity as determined by using kinase-dead human Met mutant constructs. Studies of both human liver cancer tissues and cell lines uncovered that DDD cleavage and entrapment of caspase-3 by DDD occur<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>, further proving that this site has physiological and pathophysiological relevance.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion :<\/jats:title>\n            <jats:p>\n                                 <jats:bold>Met can directly inhibit caspase-3 by way of a novel mechanism and promote hepatocyte survival. The results presented here will further our understanding of the mechanisms that control not only normal tissue homeostasis but also abnormal tissue growth such as cancer and degenerative diseases in which apoptotic caspases are at play. (Hepatology 2014;59:2010\u20132021)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26769","type":"journal-article","created":{"date-parts":[[2013,10,12]],"date-time":"2013-10-12T01:56:15Z","timestamp":1381542975000},"page":"2010-2021","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":27,"title":["Novel Death Defying Domain in Met Entraps the Active Site of Caspase-3 and Blocks Apoptosis in Hepatocytes"],"prefix":"10.1097","volume":"59","author":[{"given":"Jihong","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbin","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lida","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danushka S.","family":"Seneviratne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Kook","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Bowser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie C.","family":"DeFrances","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Zarnegar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-40-20250207","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.molmed.2005.04.005","article-title":"Cancer therapy: can the challenge be MET?","volume":"11","author":"Corso","year":"2005","journal-title":"Trends Mol Med"},{"key":"R2-40-20250207","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrc3205","article-title":"Targeting MET in cancer: rationale and progress.","volume":"12","author":"Gherardi","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"R3-40-20250207","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nrm3012","article-title":"MET signalling: principles and functions in development, organ regeneration and cancer.","volume":"11","author":"Trusolino","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"R4-40-20250207","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1083\/jcb.129.5.1177","article-title":"The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis.","volume":"129","author":"Zarnegar","year":"1995","journal-title":"J Cell Biol"},{"key":"R5-40-20250207","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1146\/annurev.biochem.68.1.383","article-title":"Mammalian caspases: structure, activation, substrates, and functions during apoptosis.","volume":"68","author":"Earnshaw","year":"1999","journal-title":"Annu Rev Biochem"},{"key":"R6-40-20250207","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1042\/BJ20041142","article-title":"The protein structures that shape caspase activity, specificity, activation and inhibition.","volume":"384","author":"FuentesPrior","year":"2004","journal-title":"Biochem J"},{"key":"R7-40-20250207","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nrc2663","article-title":"Apoptosis and cancer: the genesis of a research field.","volume":"9","author":"Cotter","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"R8-40-20250207","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation.","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"R9-40-20250207","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1471-2210-7-8","article-title":"Structural and functional definition of the specificity of a novel caspase3 inhibitor, AcDNLDCHO.","volume":"7","author":"Yoshimori","year":"2007","journal-title":"BMC Pharmacol"},{"key":"R10-40-20250207","doi-asserted-by":"crossref","first-page":"38781","DOI":"10.1074\/jbc.M605151200","article-title":"Cytokine response modifier a inhibition of initiator caspases results in covalent complex formation and dissociation of the caspase tetramer.","volume":"281","author":"Dobo","year":"2006","journal-title":"J Biol Chem"},{"key":"R11-40-20250207","doi-asserted-by":"crossref","first-page":"13274","DOI":"10.1021\/bi010574w","article-title":"Mechanismbased inactivation of caspases by the apoptotic suppressor p35.","volume":"40","author":"Riedl","year":"2001","journal-title":"Biochemistry"},{"key":"R12-40-20250207","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1042\/bj3500563","article-title":"Internally quenched fluorescent peptide substrates disclose the subsite preferences of human caspases 1, 3, 6, 7 and 8.","volume":"350","author":"Stennicke","year":"2000","journal-title":"Biochem J"},{"key":"R13-40-20250207","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1038\/sj.onc.1206933","article-title":"Cisplatin: mode of cytotoxic action and molecular basis of resistance.","volume":"22","author":"Siddik","year":"2003","journal-title":"Oncogene"},{"key":"R14-40-20250207","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0022-3565(24)29601-4","article-title":"Characterization of the caspase inhibitor IDN1965 in a model of apoptosisassociated liver injury.","volume":"297","author":"Hoglen","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"R15-40-20250207","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1084\/jem.184.5.2067","article-title":"Systemic injection of a tripeptide inhibits the intracellular activation of CPP32like proteases in vivo and fully protects mice against Fasmediated fulminant liver destruction and death.","volume":"184","author":"Rodriguez","year":"1996","journal-title":"J Exp Med"},{"key":"R16-40-20250207","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nrc1886","article-title":"Metastasis: a question of life or death.","volume":"6","author":"Mehlen","year":"2006","journal-title":"Nat Rev Cancer"},{"key":"R17-40-20250207","doi-asserted-by":"crossref","first-page":"861","DOI":"10.18388\/abp.2004_3519","article-title":"Modes of inhibition of cysteine proteases.","volume":"51","author":"Rzychon","year":"2004","journal-title":"Acta Biochim Pol"},{"key":"R18-40-20250207","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/sj.cdd.4402080","article-title":"Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor.","volume":"14","author":"Foveau","year":"2007","journal-title":"Cell Death Differ"},{"key":"R19-40-20250207","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/sj.onc.1203404","article-title":"Transcriptional activation of the hepatocyte growth factor receptor (cmet) gene by its ligand (hepatocyte growth factor) is mediated through AP1.","volume":"24","author":"Seol","year":"2000","journal-title":"Oncogene"},{"key":"R20-40-20250207","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1002\/jcb.22226","article-title":"The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.","volume":"107","author":"Dai","year":"2009","journal-title":"J Cell Biochem"},{"key":"R21-40-20250207","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1097-2765(02)00439-2","article-title":"A mechanism of cell survival: sequestration of Fas by the HGF receptor Met.","volume":"9","author":"Wang","year":"2002","journal-title":"Mol Cell"},{"key":"R22-40-20250207","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/nm1625","article-title":"Lack of Fas antagonism by Met in human fatty liver disease.","volume":"13","author":"Zou","year":"2007","journal-title":"Nat Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26769","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201405000-00040","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T16:55:30Z","timestamp":1738947330000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201405000-00040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5]]},"references-count":22,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26769","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2014,5]]}}}