title: Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching.
abstract: The serine-threonine kinase Akt is a key regulator of cell proliferation and survival, glucose metabolism, cell mobility, and tumorigenesis. Activation of Akt by extracellular stimuli such as insulin centers on the interaction of Akt with PIP3 on the plasma membrane, where it is subsequently phosphorylated and activated by upstream protein kinases. However, it is not known how Akt is recruited to the plasma membrane upon stimulation. Here we report that ubiquitin-like protein 4A (Ubl4A) plays a crucial role in insulin-induced Akt plasma membrane translocation. Ubl4A knockout newborn mice have defective Akt-dependent glycogen synthesis and increased neonatal mortality. Loss of Ubl4A results in the impairment of insulin-induced Akt translocation to the plasma membrane and activation. Akt binds actin-filaments and colocalizes with actin-related protein 2 and 3 (Arp2/3) complex in the membrane ruffles and lamellipodia. Ubl4A directly interacts with Arp2/3 to accelerate actin branching and networking, allowing Akt to be in close proximity to the plasma membrane for activation upon insulin stimulation. Our finding reveals a new mechanism by which Akt is recruited to the plasma membrane for activation, thereby providing a missing link in Akt signaling.
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616;
authors.forename: Yuting
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616;
authors.forename: Honghong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616;
authors.forename: Adriana
authors.initials: A
authors.lastname: Mañas
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tang
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637.
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637.
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Biology, Illinois Institute of Technology, Chicago, IL 60616; xiang@iit.edu.
authors.forename: Jialing
authors.initials: J
authors.lastname: Xiang
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002633:Chemotaxis / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D014452:Ubiquitins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D007328:Insulin; D014452:Ubiquitins; C000598887:Ubl4a protein, mouse; D049452:Green Fluorescent Proteins; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt translocation; Arp2/3 complex; Ubl4A; actin branching; insulin