近日，學(xué)術(shù)期刊Journal of Biological Chemistry發(fā)表了生化與細(xì)胞所李林研究組有關(guān)經(jīng)典Wnt信號(hào)途徑調(diào)節(jié)的的研究成果。這項(xiàng)研究發(fā)現(xiàn)TAB2在TAK1-NLK途徑中起著兩個(gè)激酶間腳手架蛋白質(zhì)的作用，介導(dǎo)了TAK1對(duì)NLK的激活，繼而抑制經(jīng)典Wnt信號(hào)途徑。

        經(jīng)典Wnt信號(hào)途徑在生物體的胚胎發(fā)育和一些疾病發(fā)生的過(guò)程中都發(fā)揮了十分重要的作用。經(jīng)典Wnt信號(hào)通過(guò)調(diào)節(jié)β-catenin-LEF1/TCFs轉(zhuǎn)錄復(fù)合物的形成而影響下游基因的表達(dá)變化，因此發(fā)揮各種生物學(xué)功能。而經(jīng)典Wnt信號(hào)途徑也受到多種分子和信號(hào)途徑的調(diào)節(jié)。其中TAK1-NLK非典型MAPK激酶途徑就是通過(guò)抑制β-catenin-LEF1/TCFs轉(zhuǎn)錄復(fù)合物的功能而影響Wnt信號(hào)途徑在細(xì)胞分化和發(fā)育等中的功能。TAK1和NLK分別為MAPK途徑家族的MAPKKK和MAPK分子，到目前為止，對(duì)于TAK1-NLK途徑中的激酶間信號(hào)的傳遞方式還不清楚。盡管TAK1能夠激活NLK分子的激酶活性，但是TAK1和NLK之間并沒(méi)有直接的相互作用，暗示TAK1與NLK分子間的信號(hào)傳遞可能依賴第三分子的幫助。

        李林研究組李勐博士等人研究發(fā)現(xiàn)，TAK1的一個(gè)結(jié)合蛋白質(zhì)“TAB2”能夠直接并特異性地結(jié)合NLK。TAB2結(jié)合NLK的區(qū)間處于TAB2分子的中間區(qū)域，而利用其C端區(qū)域結(jié)合TAK1分子。通過(guò)這樣的結(jié)合方式，TAB2可以作為腳手架蛋白質(zhì)與TAK1和NLK形成復(fù)合物，引起TAK1和NLK之間的一種間接的相互作用。TAB2通過(guò)介導(dǎo)這兩種蛋白激酶的相互作用而促進(jìn)了TAK1對(duì)NLK的激活，并導(dǎo)致NLK底物L(fēng)EF1/TCFs分子的磷酸化而抑制其轉(zhuǎn)錄活性。因此TAB2作為腳手架蛋白質(zhì)參與了TAK1-NLK激酶途徑的信號(hào)傳遞，對(duì)經(jīng)典Wnt信號(hào)發(fā)揮抑制作用。重要的是，當(dāng)突變TAB2導(dǎo)致降低TAB2與NLK的結(jié)合后，上述TAB2對(duì)TAK1-NLK途徑的促進(jìn)作用及對(duì)經(jīng)典Wnt信號(hào)途徑的抑制功能都大大削弱。這個(gè)研究充分的證明了TAB2作為腳手架蛋白質(zhì)在TAK1-NLK途徑抑制經(jīng)典Wnt信號(hào)途徑中的功能。在此基礎(chǔ)之上，他們還看到經(jīng)典Wnt信號(hào)也可以隨著刺激時(shí)間的增長(zhǎng)而增強(qiáng)細(xì)胞內(nèi)TAK1-TAB2-NLK復(fù)合物的形成，暗示經(jīng)典Wnt信號(hào)途徑在引起自身信號(hào)激活的同時(shí)可能激活TAK1-NLK途徑，用這種方式來(lái)抑制過(guò)度激活的信號(hào)而達(dá)到反饋抑制調(diào)節(jié)的功能。綜上所述，這些發(fā)現(xiàn)揭示了TAB2作為腳手架蛋白質(zhì)在TAK1-NLK途徑中的功能，發(fā)現(xiàn)了TAK1對(duì)NLK激活過(guò)程中的分子機(jī)制，并增進(jìn)了對(duì)經(jīng)典Wnt信號(hào)途徑的信號(hào)激活和調(diào)節(jié)方式的理解。

上海勁馬生物推薦原文出處：

JBC doi: 10.1074/jbc.M109.083246

TAB2 Scaffolds TAK1 and NLK in Repressing Canonical Wnt Signaling*
Meng Li, He Wang, Tao Huang, Jiyong Wang, Yu Ding, Zhenfei Li, Jinkuo Zhang and Lin Li1
From the State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

The TAK1-NLK cascade is a mitogen-activated protein kinase-related pathway that plays an inhibitory role in canonical Wnt/β-catenin signaling through regulating the LEF1/TCF family transcriptional factors. TAB2 （TAK1-binding protein 2） is a putative TAK1 interacting protein that is involved in the regulation of TAK1. Here, we found that TAB2 could directly interact with NLK and function as a scaffold protein to facilitate the interaction between TAK1 and NLK. Knocking down TAB2 using small interfering RNA abolished the interaction of TAK1 with NLK in mammalian cells. The intermediate region （residues 292–417） of TAB2 was mapped for its binding to NLK. TAB2-ΔM, a TAB2 mutant lacking this region, showed a lower affinity for NLK and became defective in its scaffolding function. In addition, TAB2, but not TAB2-ΔM, mediated TAK1-dependent activation of NLK and LEF1 polyubiquitylation, resulting in the inhibition of canonical Wnt signaling. Moreover, Wnt3a stimulation led to an increase in the interaction of TAB2 with NLK and the formation of a TAK1·TAB2·NLK complex, suggesting that this TAK1-TAB2-NLK pathway may constitute a negative feedback mechanism for canonical Wnt signaling.