Illario Maddalena, Monaco Sara, Cavallo Anna Lina, Esposito Iolanda, Formisano Pietro, D'Andrea Luca, Cipolletta Ersilia, Trimarco Bruno, Fenzi Gianfranco, Rossi Guido, Vitale Mario
Department of Biologia e Patologia Cellulare e Molecolare, University of Naples Federico II, Naples, Italy.
Cell Signal. 2009 May;21(5):786-92. doi: 10.1016/j.cellsig.2009.01.022. Epub 2009 Jan 9.
Cellular growth and glucose uptake are regulated by multiple signals generated by the insulin receptor. The mechanisms of individual modulation of these signals remain somewhat elusive. We investigated the role of CaMKII in insulin signalling in a rat skeletal muscle cell line, demonstrating that CaMKII modulates the insulin action on DNA synthesis and the negative feedback that down regulates glucose uptake. Insulin stimulation generated partly independent signals leading to the rapid activation of Akt, Erk-1/2 and CaMKII. Akt activation was followed by Glut-4 translocation to the plasma membrane and increase of glucose uptake. Then, IRS-1 was phosphorylated at S612, the IRS-1/p85PI3K complex was disrupted, Akt was no more phosphorylated and both Glut-4 translocation and glucose uptake were reduced. Inhibition of CaMKII abrogated the insulin-induced Erk-1/2 activation, DNA synthesis and phosphorylation of IRS-1 at S612. Inhibition of CaMKII also abrogated the down-regulation of insulin-stimulated Akt phosphorylation, Glut-4 membrane translocation and glucose uptake. These results demonstrate that: 1 - CaMKII modulates the insulin-induced Erk-1/2 activation and cell proliferation; 2 - after the initial stimulation of the IRS-1/Akt pathway, CaMKII mediates the down-regulation of stimulated glucose uptake. This represents a novel mechanism in the selective control of insulin signals, and a possible site for pharmacological intervention.
细胞生长和葡萄糖摄取受胰岛素受体产生的多种信号调控。这些信号各自的调节机制仍有些难以捉摸。我们在大鼠骨骼肌细胞系中研究了钙调蛋白激酶II（CaMKII）在胰岛素信号传导中的作用，证明CaMKII调节胰岛素对DNA合成的作用以及下调葡萄糖摄取的负反馈。胰岛素刺激产生部分独立的信号，导致Akt、细胞外调节蛋白激酶1/2（Erk-1/2）和CaMKII迅速激活。Akt激活后，葡萄糖转运蛋白4（Glut-4）转位到质膜，葡萄糖摄取增加。然后，胰岛素受体底物1（IRS-1）在丝氨酸612位点磷酸化，IRS-1/p85磷脂酰肌醇-3激酶（PI3K）复合物被破坏，Akt不再磷酸化，Glut-4转位和葡萄糖摄取均减少。抑制CaMKII可消除胰岛素诱导的Erk-1/2激活、DNA合成以及IRS-1在丝氨酸612位点的磷酸化。抑制CaMKII还可消除胰岛素刺激的Akt磷酸化、Glut-4膜转位和葡萄糖摄取的下调。这些结果表明：1 - CaMKII调节胰岛素诱导的Erk-1/2激活和细胞增殖；2 - 在IRS-1/Akt途径最初受到刺激后，CaMKII介导刺激的葡萄糖摄取的下调。这代表了胰岛素信号选择性控制中的一种新机制，以及一个可能的药物干预位点。
