Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching

Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9644-9. doi: 10.1073/pnas.1508647112. Epub 2015 Jul 20.

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.

Keywords: Akt translocation; Arp2/3 complex; Ubl4A; actin branching; insulin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin-Related Protein 2-3 Complex / metabolism*
  • Actins / metabolism
  • Animals
  • Animals, Newborn
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology*
  • Chemotaxis / drug effects
  • Embryo, Mammalian / cytology
  • Enzyme Activation / drug effects
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Glycogen / biosynthesis
  • Green Fluorescent Proteins / metabolism
  • Insulin / pharmacology*
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pseudopodia / drug effects
  • Pseudopodia / metabolism
  • Ubiquitins / deficiency
  • Ubiquitins / metabolism*

Substances

  • Actin-Related Protein 2-3 Complex
  • Actins
  • Insulin
  • Ubiquitins
  • Ubl4a protein, mouse
  • Green Fluorescent Proteins
  • Glycogen
  • Proto-Oncogene Proteins c-akt