Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation.
APS (adaptor protein with PH and SH2 domains) initiates a phosphatidylinositol 3-kinase-independent pathway involved in insulin-stimulated glucose transport. We recently identified Enigma, a PDZ and LIM domain-containing protein, as a partner of APS and showed that APS-Enigma complex plays a critical role in actin cytoskeleton organization in fibroblastic cells. Because actin rearrangement is important for insulin-induced glucose transporter 4 (Glut 4) translocation, we studied the potential involvement of Enigma in insulin-induced glucose transport in 3T3-L1 adipocytes. Enigma mRNA was expressed in differentiated adipocytes and APS and Enigma were colocalized with cortical actin. Expression of an APS mutant unable to bind Enigma increased the insulin-induced Glut 4 translocation to the plasma membrane. By contrast, overexpression of Enigma inhibited insulin-stimulated glucose transport and Glut 4 translocation without alterations in proximal insulin signaling. This inhibitory effect was prevented with the deletion of the LIM domains of Enigma. Using time-lapse fluorescent microscopy of green fluorescent protein-actin, we demonstrated that the overexpression of Enigma altered insulin-induced actin rearrangements, whereas the expression of Enigma without its LIM domains was without effect. A physiological link between increased expression of Enigma and an alteration in insulin-induced glucose uptake was suggested by the increase in Enigma mRNA expression in adipose tissue of diabetic obese patients. Taken together, these data strongly suggest that the interaction between APS and Enigma is involved in insulin-induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS/Enigma ratio could participate in the alteration of insulin-induced glucose uptake in adipose tissue.
Barrès
Romain
R
Institut National de la Santé et de la Recherche Medicale, Unité 568, Faculté de médecine, avenue de Valombrose, 06107 Nice Cedex 02, France.
Grémeaux
Thierry
T
Gual
Philippe
P
Gonzalez
Teresa
T
Gugenheim
Jean
J
Tran
Albert
A
Le Marchand-Brustel
Yannick
Y
Tanti
Jean-François
JF
D041721:3T3-L1 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000818:Animals; D003598:Cytoskeletal Proteins; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013851:Thinness / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484381:Pdlim7 protein, mouse; D012333:RNA, Messenger; C488161:Sh2b2 protein, mouse; D005947:Glucose