title: Grp1 plays a key role in linking insulin signaling to glut4 recycling.
abstract: The glucose transporter type 4 (glut4) is critical for metabolic homeostasis. Insulin regulates glut4 by modulating its expression on the cell surface. This regulation is mainly achieved by targeting the endocytic recycling of glut4. We identify general receptor for 3-phosphoinositides 1 (Grp1) as a guanine nucleotide exchange factor for ADP-ribosylation factor 6 (ARF6) that promotes glut4 vesicle formation. Grp1 also promotes the later steps of glut4 recycling through ARF6. Insulin signaling regulates Grp1 through phosphorylation by Akt. We also find that mutations that mimic constitutive phosphorylation of Grp1 can bypass upstream insulin signaling to induce glut4 recycling. Thus, we have uncovered a major mechanism by which insulin regulates glut4 recycling. Our findings also reveal the complexity by which a single small GTPase in vesicular transport can coordinate its multiple steps to accomplish a round of transport.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Malaby
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
authors.forename: David G
authors.initials: DG
authors.lastname: Lambright
authors.forename: Victor W
authors.initials: VW
authors.lastname: Hsu
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000089982:ADP-Ribosylation Factor 6; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; C495693:Slc2a4 protein, mouse; C040985:phosphatidylinositol receptors; D051057:Proto-Oncogene Proteins c-akt; D020727:ADP-Ribosylation Factors; C000715727:Arf6 protein, mouse