Rip11 is a Rab11- and AS160-RabGAP-binding protein required for insulin-stimulated glucose uptake in adipocytes

Abstract

The translocation of GLUT4 to the plasma membrane underlies the ability of insulin to stimulate glucose uptake, an event that involves the activation of protein kinase B, several members of the Rab family of GTP-binding proteins and the phosphorylation of the Rab GTPase-activating protein AS160. Here, we explored the regulation by insulin of the class I Rab11-interacting proteins Rip11, RCP and FIP2. We show that Rip11, but not RCP or FIP2, translocates to the plasma membrane of 3T3-L1 adipocytes in response to insulin. This unique response of Rip11 prompted us to explore the role of this protein in more detail. We found that Rip11 partially colocalises with GLUT4 in intracellular compartments. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated uptake of 2-deoxyglucose, and overexpression of Rip11 blocks insulin-stimulated insertion of translocated GLUT4 vesicles into the plasma membrane. We additionally show that Rip11 forms a complex with AS160 in a Rab11-independent manner and that insulin induces dissociation of AS160 from Rip11. We propose that Rip11 is an AS160- and Rab-binding protein that coordinates the protein kinase signalling and trafficking machinery required to stimulate glucose uptake in response to insulin.

Interaction of the Human Prostacyclin Receptor with Rab11

“…Moreover, the identity of the specific Rab11 effector(s), be they members of the FIPs, Rabphilin-11/RabllBP, myosin Vb, phosphoinositide 4-kinase ␤, or Sec15 (6, 56 -60), that direct the trafficking of the hIP after Rab11 activation remains to be investigated. Given the exquisite relationship that exists between certain Rab11 members and their effectors, as exemplified by Rab25 and Rab-coupling protein in coordinating the agonist-dependent recycling of the ␣5␤1 integrin (54), or Rip11 in regulating insulin-dependent GLUT 4 transport in adipocytes (61), the identification of the Rab11 effector(s) involved in the trafficking of the hIP is likely to add significantly to the understanding of the true physiologic significance of the direct interaction between the hIP and Rab11.…”

The Rab GTPase-Activating Protein AS160 as a Common Regulator of Insulin- and G.ALPHA.q-Mediated Intracellular GLUT4 Vesicle Distribution

“…it was reported that as160 showed gTPase-activating protein (gaP) activity toward rabs 2a, 8a, 10, 11 or 14. current evidence suggests that akt phosphorylation of as160 suppresses its gaP activity, and consequently increases the gTP-bound rabs and triggers an increase in the rate of gLuT4 vesicle exocytois [15][16][17][18][19]. moreover, as160 was shown to promote the retention of gLuT4 vesicles in intracellular components in 3T3L1 adipocytes [15,20].…”

Up-regulation of Cholesterol Absorption Is a Mechanism for Cholecystokinin-induced Hypercholesterolemia

“…Under steady state conditions, NPC1L1 is located predominantly in transferrin-rich recycling vesicles in the perinuclear region (27,28). Absorption of cholesterol requires translocation of NPC1L1 to the cell membrane, a process mediated by a protein complex containing Rab-GTPase-11 (Rab11) and its partner Rab11 family of interacting protein-2 (FIP2) (30,31) or other Rab11-interacting proteins (RIPs), such as Rip11 and Rab-coupling protein (32). The data from this report document the regulatory role of Rab11a in CCK-induced NPC1L1 translocation and cholesterol absorption.…”

“…The Akt-phosphorylated GAPs dissociate with the Rab11-RIP protein complex. This dissociation enables the GTP-bound form of Rab11 to drive the recycling vesicle translocation to the cell membrane (32). Insulin also has been shown to induce NPC1L1 translocation from recycling vesicles to the cell surface (28).…”

“…In addition, CCK treatment enhanced CCK1R/CCK2R heterodimerization in Caco-2 cells. Based on the findings from the current work and the known functions of the above mentioned molecules (29,32,40,41), we propose the following model to describe how CCK up-regulates cholesterol absorption (Fig. 7).…”