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首页> 外文期刊>Oncogene >HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells
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HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells

机译：HEF1是FAK的必要且特定的下游效应子，可促进胶质母细胞瘤细胞的迁移

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The highly invasive behavior of glioblastoma cells contributes to the morbidity and mortality associated with these tumors. The integrin-mediated adhesion and migration of glioblastoma cells on brain matrix proteins is enhanced by stimulation with growth factors, including platelet-derived growth factor (PDGF). As focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, has been shown to promote cell migration in various other cell types, we analysed its role in glioblastoma cell migration. Forced overexpression of FAK in serum-starved glioblastoma cells plated on recombinant (rec)-osteopontin resulted in a twofold enhancement of basal migration and a ninefold enhancement of PDGF-BB-stimulated migration. Both expression of mutant FAK(397F) and the downregulation of FAK with small interfering (si) RNA inhibited basal and PDGF-stimulated migration. FAK overexpression and PDGF stimulation was found to increase the phosphorylation of the Crk-associated substrate (CAS) family member human enhancer of filamentation 1 (HEF1), but not p130CAS or Src-interacting protein (Sin)/Efs, although the levels of expression of these proteins was similar. Moreover downregulation of HEF1 with siRNA, but not p130CAS, inhibited basal and PDGF-stimulated migration. The phosphorylated HEF1 colocalized with vinculin and was associated almost exclusively with 0.1% Triton X-100 insoluble material, consistent with its signaling at focal adhesions. FAK overexpression promoted invasion through normal brain homogenate and siHEF1 inhibited this invasion. Results presented here suggest that HEF1 acts as a necessary and specific downstream effector of FAK in the invasive behavior of glioblastoma cells and may be an effective target for treatment of these tumors.
机译：胶质母细胞瘤细胞的高度侵袭性行为导致与这些肿瘤相关的发病率和死亡率。通过用包括血小板衍生的生长因子（PDGF）在内的生长因子刺激，胶质母细胞瘤细胞在脑基质蛋白上的整合素介导的粘附和迁移得以增强。由于局灶性粘附激酶（FAK），一种非受体胞质酪氨酸激酶，已显示出能促进多种其他细胞类型的细胞迁移，因此我们分析了其在胶质母细胞瘤细胞迁移中的作用。在涂布于重组（rec）-骨桥蛋白的血清饥饿的胶质母细胞瘤细胞中FAK的过度表达导致基础迁移增加了两倍，而PDGF-BB刺激的迁移增加了九倍。突变FAK（397F）的表达和小干扰（si）RNA的FAK下调均抑制了基础和PDGF刺激的迁移。发现FAK过表达和PDGF刺激可增加Crk相关底物（CAS）家族成员丝状蛋白1（HEF1）的人类增强子的磷酸化，但不会增加p130CAS或Src相互作用蛋白（Sin）/ Efs的磷酸化，尽管表达水平这些蛋白质的相似。此外，用siRNA（而不是p130CAS）下调HEF1会抑制基础和PDGF刺激的迁移。磷酸化的HEF1与纽蛋白共定位，几乎只与0.1％Triton X-100不溶性物质相关，与其在粘着斑处的信号一致。 FAK过表达通过正常脑匀浆促进侵袭，而siHEF1抑制这种侵袭。此处给出的结果表明，HEF1在胶质母细胞瘤细胞的侵袭行为中充当FAK的必要且特定的下游效应子，并且可能是治疗这些肿瘤的有效靶标。

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