{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:36:43Z","timestamp":1760150203882,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austrian Science Fund (FWF)","award":["T1091","P31085-B26","P31383-B30"],"award-info":[{"award-number":["T1091","P31085-B26","P31383-B30"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation during or shortly after birth. In that context, activation of the AKT cell survival pathway has emerged as a promising new target for neuroprotective interventions. Here, we investigated the role of PKN1 in an in vitro model of HI, using postnatal cerebellar granule cells (Cgc) derived from Pkn1 wildtype and Pkn1\u2212\/\u2212 mice. Pkn1\u2212\/\u2212 Cgc showed significantly higher AKT phosphorylation, resulting in reduced caspase-3 activation and improved survival after HI. Pkn1\u2212\/\u2212 Cgc also showed enhanced axonal outgrowth on growth-inhibitory glial scar substrates, further pointing towards a protective phenotype of Pkn1 knockout after HI. The specific PKN1 phosphorylation site S374 was functionally relevant for the enhanced axonal outgrowth and AKT interaction. Additionally, PKN1pS374 shows a steep decrease during cerebellar development. In summary, we demonstrate the pathological relevance of the PKN1-AKT interaction in an in vitro HI model and establish the relevant PKN1 phosphorylation sites, contributing important information towards the development of specific PKN1 inhibitors.<\/jats:p>","DOI":"10.3390\/biom13111599","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T11:16:27Z","timestamp":1698750987000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PKN1 Exerts Neurodegenerative Effects in an In Vitro Model of Cerebellar Hypoxic\u2013Ischemic Encephalopathy via Inhibition of AKT\/GSK3\u03b2 Signaling"],"prefix":"10.3390","volume":"13","author":[{"given":"Stephanie","family":"zur Nedden","sequence":"first","affiliation":[{"name":"Institute of Neurobiochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motahareh Solina","family":"Safari","sequence":"additional","affiliation":[{"name":"Institute of Neurobiochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedrich","family":"Fresser","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1646-3256","authenticated-orcid":false,"given":"Klaus","family":"Faserl","sequence":"additional","affiliation":[{"name":"Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1262-9976","authenticated-orcid":false,"given":"Herbert","family":"Lindner","sequence":"additional","affiliation":[{"name":"Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"Sarg","sequence":"additional","affiliation":[{"name":"Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-8325","authenticated-orcid":false,"given":"Gottfried","family":"Baier","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Baier-Bitterlich","sequence":"additional","affiliation":[{"name":"Institute of Neurobiochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1159\/000454856","article-title":"Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy","volume":"39","author":"Lemmon","year":"2017","journal-title":"Dev. 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