蛋白质酪氨酸磷酸激酶ALK和MET的抑制剂筛选以及蛋白质酪氨酸磷酸酶PTPRU的表达与表征
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摘要
蛋白质磷酸化和去磷酸化在细胞的生长,增值,分化和转化过程中起着重要的作用,研究表明多种人类的疾病都与蛋白质磷酸酶和磷酸激酶的扩增与突变相关。
ALK和MET是两个具有代表性的受体型蛋白质酪氨酸激酶,它们的突变经常导致多种人类疾病的发生,因此,它们已成为治疗和开发靶向性药物的重要靶点。本研究以人cDNA文库为模板,分别克隆了ALK和MET的激酶结构域,并以昆虫细胞SF9为宿主,高效地表达了具有激酶活性的ALK和MET的胞内结构域,我们还建立了一套蛋白质酪氨酸磷酸激酶活性的检测系统,并研究了92种公认的蛋白质激酶抑制剂以及多种当今市场上最流行的抗癌药物对激酶活性的影响,成功的筛选到可以专一地、有效地抑制ALK激酶活性的抑制剂GO6976(IC50=30nM)和可以有效抑制MET激酶活性的抑制剂Staurosporine(IC50=20nM),并且本研究进一步利用含有ALK突变体的ALCL细胞系和NSCLC细胞系对ALK抑制剂G06976进行了表征,研究证明了该抑制剂可以在较低浓度(0.2uM-0.3uM)抑制以上细胞的生长并且有效地抑制了这两种癌细胞中主要的细胞信号通路,为研究和开发针对激酶及其突变体活性为靶点的药物奠定了研究基础。
此外,本研究还克隆了含有MAM结构域的受体型蛋白质酪氨酸磷酸酶——PTPRU的细胞内结构域。我们的研究表明,PTPRU的cadherin-like结构域在决定PTPRU在细胞中定位过程中起着主要的作用,为进一步研究该结构域在生理和病理过程中的功能提供理论依据。
Protein tyrosine kinases play an important role in regulating cell proliferation, differentiation, and transformation. Mutations of these enzymes often cause neoplastic transformation, which makes them unique markers for cancer diagnosis and specific targets for anti-cancer drug development. Alk and c-MET are two typical tyrosine kinases that are frequently mutated in cancer cells. Alk was originally identified as a fusion partner of NPM-ALK in anaplastic large cell lymphoma (ALCL). Recent studies revealed its fusion with EML4 in non-small cell lung cancer (NSCLC) and activation mutations in neuroblastoma as well. c-MET is the receptor of hepatocyte growth factor. It is mutated or over-expressed in various types of tumors including breast, liver, lung, ovary, kidney, and thyroid cancers. ALK and c-MET are hot targets for therapeutic drug development.
In this study, we cloned the catalytic domains of ALK and MET and expressed them as recombinant proteins by using the baculovirus expression system. We further established an activity assay method and used it to identify inhibitors of ALK and MET. By screening a chemical compound library containing 92 protein kinsase inhibitors, we identified GO6976 as a potent inhibitor of ALK with an IC50 value of 30 nM and staurosporine as a MET inhibitor with an IC50 value of 20 nM. We further characterized the ALK inhibitor GO6976 with NPM-ALK-positive Karpas 299 ALCL cells and EML4-ALK- positive H2228 NSCLC cells. Our data demonstrated that Go6976, at sub-micromolar concentrations, effectively blocked the growth of Karpas 299 and H2228 cells and inhibited activations of major signal transduction pathways within the cells. Together, we not only identified potent inhibitors of Alk and c-MET but also established a good system for further endeavors to identify more selective and potent protein tyrosine kinases inhibitors with therapeutic potentials.
PTPRU is a MAM domain-containing receptor-like protein tyrosine phosphatase. Previous studies demonstrated an important role of the enzyme in the maintenance of epithelial integrity and in regulation of the Wnt/β-catenin signaling pathway. To better understand the function of PTPRU, we cloned and expressed the intracellular portion of PTPRU as a GST fusion protein in E. coli cells. We purified the protein to homogeneity and used it to immunize mice for antibody production. The resultant antibodies specifically recognized PTPRU over-expressed in cell lines. Western blotting analyses demonstrated the partition of truncated forms of PTPRU containing the cadherin-like domain in the Triton X-100-insoluble fraction, and immunofluorescent cell staining revealed localization of these proteins in the punctate intracellular structures. Our data suggest that the cadherin-like domain of PTPRU has a major role in determining its intracellular localization.
ALK和MET是两个具有代表性的受体型蛋白质酪氨酸激酶,它们的突变经常导致多种人类疾病的发生,因此,它们已成为治疗和开发靶向性药物的重要靶点。本研究以人cDNA文库为模板,分别克隆了ALK和MET的激酶结构域,并以昆虫细胞SF9为宿主,高效地表达了具有激酶活性的ALK和MET的胞内结构域,我们还建立了一套蛋白质酪氨酸磷酸激酶活性的检测系统,并研究了92种公认的蛋白质激酶抑制剂以及多种当今市场上最流行的抗癌药物对激酶活性的影响,成功的筛选到可以专一地、有效地抑制ALK激酶活性的抑制剂GO6976(IC50=30nM)和可以有效抑制MET激酶活性的抑制剂Staurosporine(IC50=20nM),并且本研究进一步利用含有ALK突变体的ALCL细胞系和NSCLC细胞系对ALK抑制剂G06976进行了表征,研究证明了该抑制剂可以在较低浓度(0.2uM-0.3uM)抑制以上细胞的生长并且有效地抑制了这两种癌细胞中主要的细胞信号通路,为研究和开发针对激酶及其突变体活性为靶点的药物奠定了研究基础。
此外,本研究还克隆了含有MAM结构域的受体型蛋白质酪氨酸磷酸酶——PTPRU的细胞内结构域。我们的研究表明,PTPRU的cadherin-like结构域在决定PTPRU在细胞中定位过程中起着主要的作用,为进一步研究该结构域在生理和病理过程中的功能提供理论依据。
Protein tyrosine kinases play an important role in regulating cell proliferation, differentiation, and transformation. Mutations of these enzymes often cause neoplastic transformation, which makes them unique markers for cancer diagnosis and specific targets for anti-cancer drug development. Alk and c-MET are two typical tyrosine kinases that are frequently mutated in cancer cells. Alk was originally identified as a fusion partner of NPM-ALK in anaplastic large cell lymphoma (ALCL). Recent studies revealed its fusion with EML4 in non-small cell lung cancer (NSCLC) and activation mutations in neuroblastoma as well. c-MET is the receptor of hepatocyte growth factor. It is mutated or over-expressed in various types of tumors including breast, liver, lung, ovary, kidney, and thyroid cancers. ALK and c-MET are hot targets for therapeutic drug development.
In this study, we cloned the catalytic domains of ALK and MET and expressed them as recombinant proteins by using the baculovirus expression system. We further established an activity assay method and used it to identify inhibitors of ALK and MET. By screening a chemical compound library containing 92 protein kinsase inhibitors, we identified GO6976 as a potent inhibitor of ALK with an IC50 value of 30 nM and staurosporine as a MET inhibitor with an IC50 value of 20 nM. We further characterized the ALK inhibitor GO6976 with NPM-ALK-positive Karpas 299 ALCL cells and EML4-ALK- positive H2228 NSCLC cells. Our data demonstrated that Go6976, at sub-micromolar concentrations, effectively blocked the growth of Karpas 299 and H2228 cells and inhibited activations of major signal transduction pathways within the cells. Together, we not only identified potent inhibitors of Alk and c-MET but also established a good system for further endeavors to identify more selective and potent protein tyrosine kinases inhibitors with therapeutic potentials.
PTPRU is a MAM domain-containing receptor-like protein tyrosine phosphatase. Previous studies demonstrated an important role of the enzyme in the maintenance of epithelial integrity and in regulation of the Wnt/β-catenin signaling pathway. To better understand the function of PTPRU, we cloned and expressed the intracellular portion of PTPRU as a GST fusion protein in E. coli cells. We purified the protein to homogeneity and used it to immunize mice for antibody production. The resultant antibodies specifically recognized PTPRU over-expressed in cell lines. Western blotting analyses demonstrated the partition of truncated forms of PTPRU containing the cadherin-like domain in the Triton X-100-insoluble fraction, and immunofluorescent cell staining revealed localization of these proteins in the punctate intracellular structures. Our data suggest that the cadherin-like domain of PTPRU has a major role in determining its intracellular localization.
引文
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