近日,，西班牙生物醫(yī)學(xué)研究中心Patricia Sancho等人發(fā)現(xiàn)，蛋白絡(luò)氨酸激酶1B(PTP1B)的缺陷會抵抗轉(zhuǎn)化生長因子β(TGF-β)在肝細(xì)胞中引起的抑制作用,，這對研究磷酸酶在TGF-β信號通路中的角色開拓了新的思路。相關(guān)研究發(fā)表在3月16日的美國《生化周刊》（Journal of Biological Chemistry）上,。
已知轉(zhuǎn)化生長因子β(TGF-β）在肝細(xì)胞中起到了雙重角色的作用,，可以抑制癌癥生長，也可以促進(jìn)癌癥生長,。細(xì)胞因子的抑制作用之所以能夠通過生存信號的激活作用被負(fù)調(diào)控,，大多數(shù)是因為它們依賴于絡(luò)氨酸激酶的活性。
研究人員此次實驗的目標(biāo)是研究絡(luò)氨酸蛋白磷酸酶1B (PTP1B)在細(xì)胞應(yīng)答于TGF-β時的角色,。已經(jīng)發(fā)現(xiàn),，PTP1B的缺陷會影響TGF-β的抑制作用，比如細(xì)胞凋亡以及生長抑制,。PTP1B的缺陷也與Smad2/Smad3活性降低有關(guān),。
在普通的絡(luò)氨酸激酶抑制劑下，這兩種應(yīng)答反應(yīng)能夠重新恢復(fù),。當(dāng)應(yīng)答于TGF-β時,，PTP1B-/-細(xì)胞表現(xiàn)出提高的NF-κB活性。而敲除NF-κB p65亞基,，則會增強(qiáng)在Smads磷酸化和細(xì)胞凋亡反應(yīng)的細(xì)胞應(yīng)答,。有趣的是，在這個過程中,，Smad7的上調(diào)也被抑制,。
除此之外，在應(yīng)答TGF-β時，失去PTP1B會促進(jìn)一個改變的NADPH氧化酶(NOX)表達(dá)模式,，這會強(qiáng)烈的提升NOX1/NOX4比率,。當(dāng)然，這些改變可因為染料木素以及p65的敲除恢復(fù)原狀,。重要的是,，NOX1的敲除會抑制p65核內(nèi)易位，促進(jìn)Smad磷酸化,，下調(diào)Smad7水平,。
總的來說，結(jié)果表明,，PTP1B的缺陷可以通過Smads的抑制作用來抵抗TGF-β,，這個作用可以被NOX1依賴的NF-κB調(diào)節(jié)。反過來,，這會提升Smad抑制劑即Smad7的水平,，并參與NOX1上調(diào)的一個正反饋環(huán)路。（生物谷Bioon.com）
doi: 10.1074/jbc.M111.303958
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Protein tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor beta (TGF-β)-induced suppressor effects in hepatocytes
Conrad Ortiz, Laia Caja, Esther Bertran, Agueda Gonzalez-Rodriguez, Angela M. Valverde, Isabel Fabregat and Patricia Sancho.
Transforming Growth Factor-β (TGF-β）plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity.The aim of our work was to study the role of the protein tyrosine phosphatase 1B (PTP1B) on the cellular responses to TGF-β, using for this purpose immortalized neonatal hepatocytes isolated from both PTP1B+/+ and PTP1B-/- mice. We have found that PTP1B deficiency conferred resistance to TGF-βsuppressor effects, such as apoptosis and growth inhibition, correlating with lower Smad2/Smad3 activation.Both responses were recovered in the presence of the general tyrosine kinase inhibitor genistein. PTP1B-/- cells showed elevated NF-κB activation in response to TGF-β. Knockdown of the NF-κB p65 subunit increased cell response in terms of Smads phosphorylation and apoptosis. Interestingly, these effects were accompanied by inhibition of Smad7 up-regulation.In addition, lack of PTP1B promoted an altered NADPH oxidase (NOX) expression pattern in response to TGF-β, strongly increasing NOX1/NOX4 ratio, which was reverted by genistein and p65 knock-down. Importantly, NOX1 knock-down inhibited nuclear translocation of p65, promoted Smad phosphorylation and decreased Smad7 levels.In summary, our results suggest that PTP1B deficiency confers resistance to TGF-β through Smads inhibition, an effect that is mediated by NOX1-dependent NF-κB activation, which in turn, increases the level of the Smad inhibitor Smad7 and participates in a positive feed-back loop on NOX1 up-regulation
