{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:07:47Z","timestamp":1791396467020,"version":"4.3.3"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31900149"],"award-info":[{"award-number":["31900149"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2016YFD0500403"],"award-info":[{"award-number":["2016YFD0500403"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. RABV enters cells via clathrin-mediated endocytosis upon receptor binding. The detailed mechanism of this process and how it is regulated are not fully understood. Here, we carried out a high-through-put RNAi analysis and identified AP2-associated kinase 1 (AAK1), a serine\/threonine kinase, as an important cellular component in regulating the entry of RABV. AAK1 knock-down greatly inhibits RABV infection of cells, and AAK1-induced phosphorylation of threonine 156 of the \u03bc subunit of adaptor protein 2 (AP2M1) is found to be required for RABV entry. Inhibition of AAK1 kinase activity by sunitinib blocked AP2M1 phosphorylation, significantly inhibiting RABV infection and preventing RABV from entering early endosomes. In vivo studies revealed that sunitinib prolongs the survival of mice challenged with RABV street virus. Our findings indicate that AAK1 is a potential drug target for postexposure prophylaxis against rabies.<\/jats:p>","DOI":"10.3390\/v12010045","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T03:28:53Z","timestamp":1578022133000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["The Serine\/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry"],"prefix":"10.3390","volume":"12","author":[{"given":"Chong","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinliang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2122-8365","authenticated-orcid":false,"given":"Lei","family":"Shuai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiye","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinying","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3112-0243","authenticated-orcid":false,"given":"Zhiyuan","family":"Wen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigao","family":"Bu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China"},{"name":"Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"ref_1","unstructured":"WHO (2018, September 26). World Health Organization. Available online: http:\/\/www.who.int\/news-room\/feature-stories\/detail\/education-is-vital-to-prevent-rabies-deaths."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jackson, A.C. (2013). Human Disease. Rabies, Elsevier. [3rd ed.].","DOI":"10.1016\/B978-0-12-396547-9.00007-9"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.aivir.2019.05.003","article-title":"Structural and cellular biology of rhabdovirus entry","volume":"104","author":"Belot","year":"2019","journal-title":"Adv. Virus Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.virusres.2019.02.006","article-title":"Early events in rabies virus infection-Attachment, entry, and intracellular trafficking","volume":"263","author":"Guo","year":"2019","journal-title":"Virus Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11637","DOI":"10.1128\/JVI.01648-13","article-title":"Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin","volume":"87","author":"Piccinotti","year":"2013","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1083\/jcb.150.3.601","article-title":"Rabies Virus-Induced Membrane Fusion Pathway","volume":"150","author":"Gaudin","year":"2000","journal-title":"J. Cell Boil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8746","DOI":"10.1128\/JVI.78.16.8746-8752.2004","article-title":"Evidence that Rabies Virus Forms Different Kinds of Fusion Machines with Different pH Thresholds for Fusion","volume":"78","author":"Roche","year":"2004","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev.cellbio.20.010403.104543","article-title":"Adaptors For Clathrin Coats: Structure and Function","volume":"20","author":"Owen","year":"2004","journal-title":"Annu. Rev. Cell Dev. Boil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nrm3266","article-title":"Dynamin, a membrane-remodelling GTPase","volume":"13","author":"Ferguson","year":"2012","journal-title":"Nat. Rev. Mol. Cell Boil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1146\/annurev-cellbio-100109-104016","article-title":"Dynamin: Functional Design of a Membrane Fission Catalyst","volume":"27","author":"Schmid","year":"2011","journal-title":"Annu. Rev. Cell Dev. Boil."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.antiviral.2015.06.011","article-title":"Genetically modified rabies virus ERA strain is safe and induces long-lasting protective immune response in dogs after oral vaccination","volume":"121","author":"Shuai","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, J., Wang, Z., Liu, R., Shuai, L., Wang, X., Luo, J., Wang, C., Chen, W., Wang, X., and Ge, J. (2018). Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007189"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1083\/jcb.200108123","article-title":"Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis","volume":"156","author":"Conner","year":"2002","journal-title":"J. Cell Boil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1158\/1078-0432.CCR-06-2328","article-title":"Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma","volume":"13","author":"Goodman","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nbt1358","article-title":"A quantitative analysis of kinase inhibitor selectivity","volume":"26","author":"Karaman","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1046\/j.1398-9219.2003.0142.x","article-title":"AAK1-mediated micro2 phosphorylation is stimulated by assembled clathrin","volume":"4","author":"Conner","year":"2003","journal-title":"Traffic"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1083\/jcb.200111068","article-title":"Phosphorylation of the AP2 \u03bc subunit by AAK1 mediates high affinity binding to membrane protein sorting signals","volume":"156","author":"Ricotta","year":"2002","journal-title":"J. Cell Boil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5476","DOI":"10.1074\/jbc.M009516200","article-title":"Binding of AP2 to sorting signals is modulated by AP2 phosphorylation","volume":"276","author":"Fingerhut","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1111\/j.1600-0854.2005.00346.x","article-title":"Multiple Roles for Cyclin G-Associated Kinase in Clathrin-Mediated Sorting Events","volume":"6","author":"Zhang","year":"2005","journal-title":"Traffic"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0960-9822(01)00240-8","article-title":"Phosphorylation of threonine 156 of the mu2 subunit of the AP2 complex is essential for endocytosis in vitro and in vivo","volume":"11","author":"Olusanya","year":"2001","journal-title":"Curr. Boil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8241","DOI":"10.1128\/JVI.00519-11","article-title":"Newcastle Disease Virus-Vectored Rabies Vaccine Is Safe, Highly Immunogenic, and Provides Long-Lasting Protection in Dogs and Cats","volume":"85","author":"Ge","year":"2011","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm3151","article-title":"Molecular mechanism and physiological functions of clathrin-mediated endocytosis","volume":"12","author":"McMahon","year":"2011","journal-title":"Nat. Rev. Mol. Cell Boil."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cureton, D.K., Massol, R.H., Saffarian, S., Kirchhausen, T.L., and Whelan, S.P.J. (2009). Vesicular Stomatitis Virus Enters Cells through Vesicles Incompletely Coated with Clathrin That Depend upon Actin for Internalization. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000394"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/978-1-4614-7651-1_4","article-title":"Entry of influenza virus","volume":"790","author":"Sun","year":"2013","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1083\/jcb.200112067","article-title":"Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake","volume":"158","author":"Meier","year":"2002","journal-title":"J. Cell Boil."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1073\/pnas.1117949109","article-title":"Basolateral sorting of the coxsackie and adenovirus receptor through interaction of a canonical YXX\u03a6 motif with the clathrin adaptors AP-1A and AP-1B","volume":"109","author":"Gravotta","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.virol.2007.07.021","article-title":"Productive entry of type C foot-and-mouth disease virus into susceptible cultured cells requires clathrin and is dependent on the presence of plasma membrane cholesterol","volume":"369","author":"Sandvig","year":"2007","journal-title":"Virology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1126\/science.7053569","article-title":"Is the acetylcholine receptor a rabies virus receptor?","volume":"215","author":"Lentz","year":"1982","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7181","DOI":"10.1128\/JVI.72.9.7181-7190.1998","article-title":"The Neural Cell Adhesion Molecule Is a Receptor for Rabies Virus","volume":"72","author":"Thoulouze","year":"1998","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7250","DOI":"10.1093\/emboj\/17.24.7250","article-title":"Low-affinity nerve-growth factor receptor (P75NTR) can serve as a receptor for rabies virus","volume":"17","author":"Tuffereau","year":"1998","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1111\/j.1600-0854.2007.00645.x","article-title":"Neurotrophins Redirect p75NTRfrom a Clathrin-Independent to a Clathrin-Dependent Endocytic Pathway Coupled to Axonal Transport","volume":"8","author":"Deinhardt","year":"2007","journal-title":"Traffic"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1046\/j.0953-816x.2000.01439.x","article-title":"Neural cell adhesion molecule is endocytosed via a clathrin-dependent pathway","volume":"13","author":"Duran","year":"2001","journal-title":"Eur. J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Piccinotti, S., and Whelan, S.P.J. (2016). Rabies Internalizes into Primary Peripheral Neurons via Clathrin Coated Pits and Requires Fusion at the Cell Body. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005753"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1146\/annurev-biochem-060208-104626","article-title":"Virus Entry by Endocytosis","volume":"79","author":"Mercer","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1128\/JVI.01864-08","article-title":"Host cell factors and functions involved in vesicular stomatitis virus entry","volume":"83","author":"Johannsdottir","year":"2009","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1083\/jcb.200304069","article-title":"Differential requirements for AP-2 in clathrin-mediated endocytosis","volume":"162","author":"Conner","year":"2003","journal-title":"J. Cell Boil."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4387","DOI":"10.1128\/JVI.02705-14","article-title":"AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets","volume":"89","author":"Neveu","year":"2015","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Neveu, G., Barouch-Bentov, R., Ziv-Av, A., Gerber, R., Jacob, Y., and Einav, S. (2012). Identification and Targeting of an Interaction between a Tyrosine Motif within Hepatitis C Virus Core Protein and AP2M1 Essential for Viral Assembly. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002845"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e02233-17","DOI":"10.1128\/mBio.02233-17","article-title":"Interactions between the Hepatitis C Virus Nonstructural 2 Protein and Host Adaptor Proteins 1 and 4 Orchestrate Virus Release","volume":"9","author":"Xiao","year":"2018","journal-title":"mBio"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1172\/JCI89857","article-title":"Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects","volume":"127","author":"Bekerman","year":"2017","journal-title":"J. Clin. Investig."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/45\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:46:50Z","timestamp":1760190410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/45"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,30]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["v12010045"],"URL":"https:\/\/doi.org\/10.3390\/v12010045","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,30]]}}}