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Classic three-tier MAPK signaling relies on MAP3K→MAP2K→MAPK activation, while upstream regulation may include MAP kinase kinase kinase kinase (MAP4K) activity. MAP4K4 is a widely studied MAP4K member implicated in inflammatory, cardiovascular, and malignant diseases, shaping proliferation, transformation, invasiveness, adhesion, stress responses, and migration. 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Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases. Cancers 2023, 15, 2272. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cancers15082272](10.3390/cancers15082272)  \nReceived: 16 March 2023  \nAccepted: 11 April 2023  \nPublished: 13 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA  \n2 UICentre for Drug Discovery, University of Illinois at Chicago, Chicago, IL 60612, USA  \n3 University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA  \n4 Jesse Brown VA Medical Center, Chicago, IL 60612, USA  \n* Correspondence: [singhsk@uic.edu](singhsk@uic.edu) (S.K.S.); [arana@uic.edu](arana@uic.edu) (A.R.); Tel.: +1-312-413-7358 (S.K.S.);+1-312-413-7271 (A.R.)  \n† These authors contributed equally to this work.  \nSimple Summary: The mitogen-activated protein kinase (MAPK) pathway plays a crucial role in inflammatory and malignant diseases. The MAPK signaling cascade is mediated by various members of the MAP4K, MAP3K, MAP2K, and MAPK families. One of the members of the MAP4K family, MAP4K4, is emerging as a critical player in non-malignant and malignant diseases. MAP4K4 has been investigated for its regulatory role in metabolic and inflammatory diseases and various cancers. Recent understanding of MAP4K4 in malignant diseases suggests a critical role of MAP4K4 in glioblastoma, colon, prostate and pancreatic cancers and associated cachexia. Based on the significant role of MAP4K4 in inflammatory and malignant diseases, it can be utilized as a viable target for therapeutic intervention.  \nAbstract: Mitogen-activated protein kinase (MAPK) cascades are crucial in extracellular signal transduction to cellular responses. 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-50-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.  \nKeywords: mitogen-activated protein kinase; MAP4K4; inflammation; immunity; cancer  \n1. Introduction  \nMitogen-activated protein kinase (MAPK) cascades are key in transducing extracellular signals to cellular responses. The MAPK signaling is a cumulative outcome of multilayered regulation by MAPK upstream regulators, incl","cbCaifByCCDHtTzs","https://ap.wps.com/l/cbCaifByCCDHtTzs","pdf",1930215,16,"English","# Introduction\n## MAPK signaling cascades and activation\n## MAPK subfamilies and phosphorylation regulation\n## MAP3K and upstream control of MAP2Ks","[{\"question\":\"Why is MAP4K4 considered relevant for cancer therapy?\",\"answer\":\"MAP4K4 overexpression is reported in multiple cancers, including glioblastoma, colon, prostate, and pancreatic cancers. The review also highlights links to cancer-associated cachexia and proposes MAP4K4 as a viable target for therapeutic intervention.\"}]","Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases | PDF",1790250076]