A critical role of the small GTPase Rac1 in Akt2-mediated GLUT4 translocation in mouse skeletal muscle.
Insulin promotes glucose uptake in skeletal muscle by inducing the translocation of the glucose transporter GLUT4 to the plasma membrane. The serine/threonine kinase Akt2 has been implicated as a key regulator of this insulin action. However, the mechanisms whereby Akt2 regulates multiple steps of GLUT4 translocation remain incompletely understood. Recently, the small GTPase Rac1 has been identified as a skeletal muscle-specific regulator of insulin-stimulated glucose uptake. Here, we show that Rac1 is a critical downstream component of the Akt2 pathway in mouse skeletal muscle as well as cultured myocytes. GLUT4 translocation induced by constitutively activated Akt2 was totally dependent on the expression of Rac1 in L6 myocytes. Moreover, we observed the activation of Rac1 when constitutively activated Akt2 was ectopically expressed. Constitutively activated Akt2-triggered Rac1 activation was diminished by knockdown of FLJ00068, a guanine nucleotide exchange factor for Rac1. Knockdown of Akt2, on the other hand, markedly reduced Rac1 activation by a constitutively activated mutant of phosphoinositide 3-kinase. In mouse skeletal muscle, constitutively activated mutants of Akt2 and phosphoinositide 3-kinase, when ectopically expressed, induced GLUT4 translocation. Muscle-specific rac1 knockout markedly diminished Akt2- or phosphoinositide 3-kinase-induced GLUT4 translocation, highlighting a crucial role of Rac1 downstream of Akt2. Taken together, these results strongly suggest a novel regulatory link between Akt2 and Rac1 in insulin-dependent signal transduction leading to glucose uptake in skeletal muscle.
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Nobuyuki
N
Takenaka
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Rumi
R
Izawa
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Junyuan
J
Wu
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Kaho
K
Kitagawa
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Yuma
Y
Nihata
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.
Tetsuya
T
Hosooka
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.
Tetsuya
T
Noguchi
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.
Wataru
W
Ogawa
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Japan.
Atsu
A
Aiba
Laboratory of Cell Biology, Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan.
Takaya
T
Satoh
D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; C495693:Slc2a4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D005947:Glucose
Akt2; GLUT4; Rac1; insulin; skeletal muscle