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The classical three-tiered MAPK cascades include signaling through MAP kinase kinase kinase (MAP3K) that activates a MAP kinase kinase (MAP2K), which in turn induces MAPK activation and downstream cellular responses. The upstream activators of MAP3K are often small guanosine-5\u2032-triphosphate (GTP)-binding proteins, but in some pathways, MAP3K can be activated by another kinase, which is known as a MAP kinase kinase kinase kinase (MAP4K). MAP4K4 is one of the widely studied MAP4K members, known to play a significant role in inflammatory, cardiovascular, and malignant diseases. The MAP4K4 signal transduction plays an essential role in cell proliferation, transformation, invasiveness, adhesiveness, inflammation, stress responses, and cell migration. Overexpression of MAP4K4 is frequently reported in many cancers, including glioblastoma, colon, prostate, and pancreatic cancers. Besides its mainstay pro-survival role in various malignancies, MAP4K4 has been implicated in cancer-associated cachexia. In the present review, we discuss the functional role of MAP4K4 in malignant\/non-malignant diseases and cancer-associated cachexia and its possible use in targeted therapy.<\/jats:p>","DOI":"10.3390\/cancers15082272","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T01:35:00Z","timestamp":1681349700000},"page":"2272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7639-9212","authenticated-orcid":false,"given":"Sunil Kumar","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Roy","sequence":"additional","affiliation":[{"name":"UICentre for Drug Discovery, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-9392","authenticated-orcid":false,"given":"Piush","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saket","family":"Jha","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basabi","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1126\/science.1072682","article-title":"Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases","volume":"298","author":"Johnson","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1002\/pro.2374","article-title":"Molecular basis of MAP kinase regulation","volume":"22","author":"Peti","year":"2013","journal-title":"Protein Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.4161\/cc.6.21.4930","article-title":"Canonical and alternative MAPK signaling","volume":"6","author":"Pimienta","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1038\/sj.onc.1210415","article-title":"MAP kinases and the control of nuclear events","volume":"26","author":"Turjanski","year":"2007","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nri2035","article-title":"MAPK phosphatases\u2014Regulating the immune response","volume":"7","author":"Liu","year":"2007","journal-title":"Nat. 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