TGF-β-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-β1-induced MKK3-p38 MAPK activation and stimulation of type I collagen
TGF-β-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-β1-induced MKK3-p38 MAPK activation and stimulation of type I collagen
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DOI：
10.1152/ajprenal.00485.2006
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发表时间：
2007-05-01
影响因子：
4.2
通讯作者：
Choi, Mary E.
中科院分区：
文献类型：
--
作者：
Kim, Sung Il;Kwak, Joon Hyeok;Choi, Mary E.
我们之前已经证明，转化生长因子- β (1) （tgf - β(1)）快速激活丝裂原激活的蛋白激酶激酶3 (MKK3)-p38 MAPK信号级联，导致小鼠肾小球系膜细胞中I型胶原合成的诱导（Wang L, Ma R, Flavell RA, Choi ME）。中国生物医学工程学报（英文版），2002)。在本研究中，我们研究了上游tgf - β活化激酶1 （TAK1）和TAK1结合蛋白1 （TAB1）在tgf - β(1)信号级联中的功能作用。在小鼠系膜细胞中观察到tgf - β(1)快速激活内源性TAK1活性。TAK1与TAB1的短暂过表达在tgf - β(1)刺激或不刺激的情况下增强了MKK3和p38 MAPK的激活，而TAK1的显性负突变体（TAK1DN）抑制了tgf - β(1)诱导的MKK3和p38 MAPK的激活。此外，TAK1DN的组成性表达降低了MKK3和p38 MAPK的稳态蛋白水平以及MKK3的磷酸化。通过异位表达TAB1或野生型p38 α MAPK增加p38 α MAPK活性，导致tgf - β(1)诱导的I型胶原表达增强。相反，TAK1DN的组成性表达抑制胶原诱导。综上所述，我们的数据表明，TAK1和TAB1作为上游信号转导发挥关键作用，激活MKK3-p38 MAPK信号级联，导致tgf - β诱导I型胶原表达(1)。此外，我们的研究结果还表明TAK1在调节MKK3和p38 MAPK的稳态蛋白水平方面具有新的功能。
We have previously demonstrated that transforming growth factor-beta(1) (TGF-beta(1)) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257-47262, 2002). In the present study, we investigated the functional role of upstream TGF-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-beta(1) signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-beta(1) was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-beta(1) stimulation, whereas a dominant- negative mutant of TAK1 (TAK1DN) suppressed TGF-beta(1)-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38 alpha MAPK activity by ectopic expression of either TAB1 or wild- type p38 alpha MAPK resulted in enhanced TGF-beta(1)-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steadystate protein levels of MKK3 and p38 MAPK.