{"id":879,"date":"2026-02-01T19:18:09","date_gmt":"2026-02-01T19:18:09","guid":{"rendered":"http:\/\/changingfaceofamerica.com\/?p=879"},"modified":"2026-02-01T19:18:09","modified_gmt":"2026-02-01T19:18:09","slug":"c6-but-not-d5-induced-mitochondrial-membrane-depolarization-in-her4-jma-cyt1transfected-bt549-cells-figure6b-as-observed-with-nrg1-figure3e","status":"publish","type":"post","link":"https:\/\/changingfaceofamerica.com\/?p=879","title":{"rendered":"\ufeffC6, but not D5, induced mitochondrial membrane depolarization in HER4 JMa\/CYT1transfected BT549 cells (Figure6B), as observed with NRG1 (Figure3E)"},"content":{"rendered":"

\ufeffC6, but not D5, induced mitochondrial membrane depolarization in HER4 JMa\/CYT1transfected BT549 cells (Figure6B), as observed with NRG1 (Figure3E). trafficking to mitochondria with antiHER4 Abs to mimic NRG1 suppressor functions could be an alternative 5,6-Dihydrouridine anticancer strategy. Keywords:4ICD, antibody, cancer, HER4, neuregulin Neuregulin 1 (NRG1) induced cleavage of poly(ADPribose) polymerase (PARP) in human epidermal growth factor receptor 4 (HER4) JMa\/CYT1expressing cancer cells. NRG1 favored HER4 intracellular domain (4ICD) cleavage and retention into mitochondria leading to reactive oxygen species (ROS) production through mitochondrial depolarization in HER4 JMa\/CYT1expressing cancer cells. Phagedisplayed selected antiHER4 Ab C6 induced 4ICD 5,6-Dihydrouridine<\/a> cleavage and retention into mitochondria, mimicking NRG1mediated effects on PARP cleavage, ROS production, and mitochondrial membrane depolarization. C6 Ab reduced in vivo growth of ovarian COV434 and breast HCC1187 tumor cell xenografts in nude mice. == Abbreviations == HER4 intracellular domain carbonyl cyanide mchlorophenyl hydrazone extracellular domain epidermal growth factor receptor Gprotein coupled receptor human epidermal growth factor receptor intracellular domain Institut rgional du Cancer de Montpellier neuregulin 1 poly(ADPribose) polymerase phycoerythrin reactive oxygen species receptor tyrosine kinase tertbutyl hydroperoxide triplenegative breast cancer == 1. INTRODUCTION == The human epidermal growth factor receptor family Rabbit polyclonal to BMPR2<\/a> (HER or ErbB) includes 4 RTKs (EGFR\/HER1, HER2, HER3, and HER4) that play roles in development and cancer. The roles of EGFR and HER2 in cancer progression led to the development of mAbs against these receptors, such as cetuximab and trastuzumab.1More recently, HER3 has been considered a key player in tumor signaling and resistance to cancer drugs, leading to the 5,6-Dihydrouridine development of antiHER3 mAbs.2Conversely, results with antagonist mAbs against HER4 have been disappointing, and currently no antiHER4 mAb is used in the clinic. Among HER members, HER4 is unusual. Its biology is more complex and its role in cancer is still controversial. It is expressed in various cancers, such as blastoma, breast, lung, melanoma, pancreas, gastric, colorectal, ovarian, and bladder cancer.3However, the prognostic significance ofHER4expression in cancer remains unclear, particularly in breast cancer whereHER4has been alternatively described as an oncogene4and a tumor suppressor.5These opposite effects are explained by the existence of 4 HER4 isoforms at the cell surface, each with its own downstream signaling pathway.6These isoforms (JMa\/CYT1, JMa\/CYT2, JMb\/CYT1, and JMb\/CYT2) differ in their ECD and ICD. Following activation, JMa isoforms are cleaved by a 2step process, catalyzed by tumor necrosis factor converting enzyme and then secretase and called regulated intramembrane proteolysis, to release the HER4 ECD and ICD (4ICD).7The HER4 intracellular domain translocates to the nucleus where it acts on gene transcription to control multiple cellular pathways (differentiation, migration, and proliferation).8Conversely, JMb isoforms are not cleaved and act as classical RTKs. The HER4 isoforms acquire the cytoplasmic domain CYT1 or CYT2 by alternative splicing.9CYT2 isoforms can only induce phosphorylation of MAPK pathway components, whereas the 16a.a. extension present only in CYT1 isoforms allows the activation of the MAPK and PI3K pathways.10 Most studies describe HER4 isoforms and their main ligand NRG1 as oncogenes. JMa\/CYT1 and JMa\/CYT2 are widely coexpressed. Conversely, expression of JMb variants seems to be restricted to some tissues.6In cancer, JMa\/CYT1 and JMa\/CYT2 have been associated with poor prognosis, due to 4ICD translocation to the nucleus.11JMa\/CYT1 has been implicated in tumor progression,12and JMa\/CYT2 is considered the most oncogenic isoform. Indeed, CYT2 is more stable than CYT1 in the cytosol,13and its nuclear location is more robust, with better transcriptional activity.14Moreover, CYT2 can activate hyperplasiarelated pathways, such as Wnt, catenin, and KITENIN,15and JMa\/CYT2 homodimers are constitutively phosphorylated to promote ligandindependent growth.16Both isoforms support cancer cell proliferation by modulating numerous signaling pathways.17 However, in breast cancer, CYT1 isoforms have also been associated with inhibition of cancer cell proliferation.18In the cytosol of breast cancer cells,.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffC6, but not D5, induced mitochondrial membrane depolarization in HER4 JMa\/CYT1transfected BT549 cells (Figure6B), as observed with NRG1 (Figure3E). trafficking to mitochondria with antiHER4 Abs to mimic NRG1 suppressor functions could be an alternative 5,6-Dihydrouridine anticancer strategy. Keywords:4ICD, antibody, cancer, HER4, neuregulin Neuregulin 1 (NRG1) induced cleavage of poly(ADPribose) polymerase (PARP) in human epidermal growth […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[12],"tags":[],"class_list":["post-879","post","type-post","status-publish","format-standard","hentry","category-thyrotropin-releasing-hormone-receptors"],"_links":{"self":[{"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/879","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=879"}],"version-history":[{"count":1,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/879\/revisions"}],"predecessor-version":[{"id":880,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/879\/revisions\/880"}],"wp:attachment":[{"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=879"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=879"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=879"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}