近日，西班牙生物医学研究中心Patricia Sancho等人发现，蛋白络氨酸激酶1B(PTP1B)的缺陷会抵抗转化生长因子β(TGF-β)在肝细胞中引起的抑制作用，这对研究磷酸酶在TGF-β信号通路中的角色开拓了新的思路。相关研究发表在3月16日的美国《生化周刊》（Journal of Biological Chemistry）上。
已知转化生长因子β(TGF-β）在肝细胞中起到了双重角色的作用，可以抑制癌症生长，也可以促进癌症生长。细胞因子的抑制作用之所以能够通过生存信号的激活作用被负调控，大多数是因为它们依赖于络氨酸激酶的活性。
研究人员此次实验的目标是研究络氨酸蛋白磷酸酶1B (PTP1B)在细胞应答于TGF-β时的角色。已经发现，PTP1B的缺陷会影响TGF-β的抑制作用，比如细胞凋亡以及生长抑制。PTP1B的缺陷也与Smad2/Smad3活性降低有关。
在普通的络氨酸激酶抑制剂下，这两种应答反应能够重新恢复。当应答于TGF-β时，PTP1B-/-细胞表现出提高的NF-κB活性。而敲除NF-κB p65亚基，则会增强在Smads磷酸化和细胞凋亡反应的细胞应答。有趣的是，在这个过程中，Smad7的上调也被抑制。
除此之外，在应答TGF-β时，失去PTP1B会促进一个改变的NADPH氧化酶(NOX)表达模式，这会强烈的提升NOX1/NOX4比率。当然，这些改变可因为染料木素以及p65的敲除恢复原状。重要的是，NOX1的敲除会抑制p65核内易位，促进Smad磷酸化，下调Smad7水平。
总的来说，结果表明，PTP1B的缺陷可以通过Smads的抑制作用来抵抗TGF-β，这个作用可以被NOX1依赖的NF-κB调节。反过来，这会提升Smad抑制剂即Smad7的水平，并参与NOX1上调的一个正反馈环路。（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
