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A critical role of the small GTP ase Rac1 in Akt2‐mediated GLUT 4 translocation in mouse skeletal muscle
Author(s) -
Takenaka Nobuyuki,
Izawa Rumi,
Wu Junyuan,
Kitagawa Kaho,
Nihata Yuma,
Hosooka Tetsuya,
Noguchi Tetsuya,
Ogawa Wataru,
Aiba Atsu,
Satoh Takaya
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12719
Subject(s) - rac1 , chromosomal translocation , microbiology and biotechnology , gtp' , chemistry , skeletal muscle , biology , biochemistry , endocrinology , signal transduction , gene , enzyme
Insulin promotes glucose uptake in skeletal muscle by inducing the translocation of the glucose transporter GLUT 4 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 GLUT 4 translocation remain incompletely understood. Recently, the small GTP ase 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. GLUT 4 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 FLJ 00068, 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 GLUT 4 translocation. Muscle‐specific rac1 knockout markedly diminished Akt2‐ or phosphoinositide 3‐kinase‐induced GLUT 4 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.