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首页> 外文期刊>Molecular and Cellular Biology >Transforming Growth Factor β (TGF-β)-Smad Target Gene Protein Tyrosine Phosphatase Receptor Type Kappa Is Required for TGF-β Function
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Transforming Growth Factor β (TGF-β)-Smad Target Gene Protein Tyrosine Phosphatase Receptor Type Kappa Is Required for TGF-β Function

机译：TGF-β功能需要转化生长因子β（TGF-β）-Smad靶基因蛋白酪氨酸磷酸酶受体类型Kappa

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摘要

Transforming growth factor β (TGF-β) inhibits proliferation and promotes cell migration. In TGF-β-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-β up-regulated PTPRK mRNA and RPTPκ (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-β-mediated antimitogenesis. Endogenous RPTPκ associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-β enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTPκ was eliminated by RNA interference (RNAi). In cells expressing RPTPκ RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTPκ positively regulates Src; (ii) HER2 signaling and TGF-β-induced RPTPκ converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTPκ is required for both the antiproliferative and the promigratory effects of TGF-β.
机译：转化生长因子β（TGF-β）抑制增殖并促进细胞迁移。在TGF-β处理的MCF10A过表达HER2的乳腺上皮细胞中，通过染色质免疫沉淀，我们确定了新型Smad目标，包括蛋白酪氨酸磷酸酶受体类型Kappa（PTPRK）。 TGF-β在肿瘤和非肿瘤乳腺细胞中上调了PTPRK mRNA和RPTPκ（受体型蛋白酪氨酸磷酸酶κ，PTPRK基因编码的蛋白产物）蛋白; HER2过表达下调其表达。 PTPRK的RNA干扰（RNAi）加速了细胞周期进程，增强了对表皮生长因子（EGF）的反应，并废除了TGF-β介导的抗有丝分裂作用。内源性RPTPκ与EGF受体和HER2相关，导致基底和ErbB配体诱导的增殖和受体磷酸化受到抑制。在MCF10A / HER2细胞中，TGF-β增强细胞运动性，FAK磷酸化，F-肌动蛋白装配和粘着斑形成并抑制RhoA活性。当通过RNA干扰（RNAi）消除RPTPκ时，这些反应就消失了。在表达RPTPκRNAi的细胞中，Tyr527处Src的磷酸化增加，而Tyr416处Src的（激活）磷酸化减少。这些数据表明：（i）RPTPκ正调控Src; （ii）HER2信号和TGF-β诱导的RPTPκ在Src处收敛，为激活FAK和增加细胞运动性和粘附性提供了足够的输入; （iii）RPTPκ是TGF-β的抗增殖和迁移作用所必需的。

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