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Dev Cell. 2012 Jun 12;22(6):1286-98. doi: 10.1016/j.devcel.2012.03.004. Epub 2012 May 17.

Grp1 plays a key role in linking insulin signaling to glut4 recycling.

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  • 1Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.


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.

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