MKK6/3 and p38 MAPK pathway activation is not necessary for insulin-induced glucose uptake but regulates glucose transporter expression
MKK6/3 and p38 MAPK pathway activation is not necessary for insulin-induced glucose uptake but regulates glucose transporter expression
复制标题
DOI：
10.1074/jbc.m101087200
复制
发表时间：
2001-06-08
影响因子：
4.8
通讯作者：
Asano, T
中科院分区：
文献类型：
--
作者：
Fujishiro, M;Gotoh, Y;Asano, T
p38丝裂原活化蛋白激酶（MAPK）位于MAPK激酶（MKK）6和MKK 3的下游，通过促有丝分裂或应激诱导刺激以及胰岛素活化。为了阐明MKK 6/3-p38 MAPK通路在葡萄糖转运调节中的作用，使用腺病毒介导的转染程序在3 T3-L1脂肪细胞和L 6肌管中过表达显性负性p38 MAPK和MKK 6突变体以及组成型活性MKK 6和MKK 3突变体。组成型活性MKK 6/3突变体上调GLUT 1表达和下调GLUT 4表达，从而显著增加基础葡萄糖转运，但减少胰岛素诱导的转运。慢性（24小时）暴露于肿瘤坏死因子α、白细胞介素-1 β或200 mM山梨醇也引起类似的效应，所有这些都激活MKK 6/3-p38 MAPK通路。SB 203580，一种特异性p38 MAPK抑制剂，减弱了这些作用，进一步证实MMK 6和MMK 3都通过p38 MAPK起作用，而它们对由组成型活性MAPK激酶1（MEK 1）突变体或肉豆蔻酰化Akt诱导的葡萄糖转运增加没有作用。通过显性失活p38 MAPK或MKK 6突变体的过表达抑制p38 MAPK活化并不减少胰岛素诱导的3 T3-L1脂肪细胞的葡萄糖摄取，因此，显然p38 MAPK的激活对于胰岛素诱导的葡萄糖摄取增加不是必需的。相反，p38 MAPK激活导致胰岛素诱导的葡萄糖摄取通过GLUT 4显著下调，这可能是肿瘤坏死因子α和其他因子引起的细胞应激诱导的胰岛素抵抗的基础。
p38 mitogen-activated protein kinase (MAPK), which is situated downstream of MAPK kinase (MKK) 6 and MKK3, is activated by mitogenic or stress-inducing stimuli, as well as by insulin. To clarify the role of the MKK6/3-p38 MAPK pathway in the regulation of glucose transport, dominant negative p38 MAPK and MKK6 mutants and constitutively active MKK6 and MKK3 mutants were overexpressed in 3T3-L1 adipocytes and L6 myotubes using an adenovirus-mediated transfection procedure. Constitutively active MKK6/3 mutants up-regulated GLUT1 expression and down-regulated GLUT4 expression, thereby significantly increasing basal glucose transport but diminishing transport induced by insulin. Similar effects were elicited by chronic (24 h) exposure to tumor necrosis factor alpha, interleukin-1 beta, or 200 mM sorbitol, all activate the MKK6/3-p38 MAPK pathway. SB203580, a specific p38 MAPK inhibitor, attenuated these effects, further confirming that both MMK6 and MMK3 act via p38 MAPK,whereas they had no effect on the increase in glucose transport induced by a constitutively active MAPK kinase 1 (MEK1) mutant or by myristoylated Akt, In addition, suppression of p38 MAPK activation by overexpression of a dominant negative p38 MAPK or MKK6 mutant did not diminish insulin-induced glucose uptake by 3T3-L1 adipocytes, It is thus apparent that activation of p38 MAPK is not essential for insulin-induced increases in glucose uptake. Rather, p38 MAPK activation leads to a marked down-regulation of insulin-induced glucose uptake via GLUT4, which may underlie cellular stress-induced insulin resistance caused by tumor necrosis factor alpha and other factors.