{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T01:47:15Z","timestamp":1776476835657,"version":"3.51.2"},"reference-count":160,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Culture, Sports, Science, and Technology of Japan","award":["21K09134"],"award-info":[{"award-number":["21K09134"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The basic helix\u2013loop\u2013helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)\/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5\/E3 complexes, and VHL forms a VBC-Cul2\/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin\u2013proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin\u2013proteasome system but also act directly on JAKs to suppress the Janus kinase\u2013signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor\u2013vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.<\/jats:p>","DOI":"10.3390\/ijms24043880","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T03:09:21Z","timestamp":1676430561000},"page":"3880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of SOCS and VHL Proteins in Neuronal Differentiation and Development"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4335-3899","authenticated-orcid":false,"given":"Hiroshi","family":"Kanno","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan"},{"name":"Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shutaro","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan"},{"name":"Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Yoshizumi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimihiro","family":"Nakahara","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, International University of Health and Welfare, Atami 413-0012, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuhiko","family":"Kubo","sequence":"additional","affiliation":[{"name":"Nerve Care Clinic, Yokosuka 238-0012, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidetoshi","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taro","family":"Shuin","sequence":"additional","affiliation":[{"name":"Kochi Medical School Hospital, Nangoku 783-0043, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoi-Sang","family":"U","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of California San Diego, San Diego, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/cne.901240303","article-title":"Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats","volume":"124","author":"Altman","year":"1965","journal-title":"J. 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