Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs

• Published in: Molecular biology of the cell Vol. 24; no. 16; pp. 2544 - 2557
• Main Authors: Sadacca, L Amanda, Bruno, Joanne, Wen, Jennifer, Xiong, Wenyong, McGraw, Timothy E
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 15.08.2013
• Subjects: 3T3 Cells; Adipocytes - metabolism; Animals; Cell Line; CHO Cells; Cricetulus; Cytoplasmic Vesicles - metabolism; Electroporation; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; GTPase-Activating Proteins - biosynthesis; GTPase-Activating Proteins - metabolism; Guanine Nucleotide Exchange Factors - metabolism; Insulin - metabolism; Mice; Munc18 Proteins - genetics; Munc18 Proteins - metabolism; Protein Transport; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; ral GTP-Binding Proteins - genetics; ral GTP-Binding Proteins - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e13-02-0103

Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation.