Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity.
Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity.
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通过整联蛋白介导的细胞骨架链接和配体结合亲和力调节细胞迁移。
DOI：
10.1083/jcb.134.6.1551
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发表时间：
1996-09
影响因子：
7.8
通讯作者：
Horwitz, AF
中科院分区：
文献类型：
--
作者：
Huttenlocher, A;Ginsberg, MH;Horwitz, AF
整合素细胞表面黏附受体在介导细胞迁移中起着核心作用。我们已经开发了一个由异位表达αIIbβ3整合素的CHO细胞组成的模型系统，以研究细胞迁移过程中整合素的亲和力和细胞骨架的相互作用。整合素αIIbβ3适合于研究细胞迁移过程中的整合素受体，因为它们在配体结合、细胞骨架相互作用和信号转导方面具有很好的特性，并且可以获得受体功能改变的突变体。αIIbβ3受体特异性地介导了转染αIIbβ3的CHO细胞的迁移。以纤维蛋白原为底物，用时间推移显微镜、随机和透射法研究了CHO细胞在纤维蛋白原上的迁移。同位移位分析和随机跨井分析测量了迁移的不同方面，其中随机跨井分析与时间推移视频显微镜最密切相关。细胞质区域的突变增加了配体的亲和力，或者通过LIBS6抗体将αIIbβ3受体激活到高亲和力状态，从而降低了迁移率。同样，在不影响亲和力的情况下增加细胞骨架组织的突变也降低了迁移率。相反，截断β链会改变细胞骨架的关联性，这是通过没有局部粘连来检测的，它减少了触觉迁移，同时增加了随机迁移。通过改变底物浓度，这些对迁移率的影响被部分补偿，展示了支持最大迁移量的最佳底物浓度。例如，与表达低亲和力受体的细胞相比，表达高亲和力整合素的细胞在较低的底物浓度下表现出最大的迁移。综上所述，这些结果表明，细胞和底物之间的黏附强度受到受体亲和力、黏附复合体的组织和底物浓度的调节，是细胞迁移速度的重要调节因素。此外，我们证明了高亲和力整合素在抑制迁移方面的主导作用，而不考虑黏附复合体的组织。这些观察结果对肿瘤转移及其治疗具有潜在的指导意义。
Integrin cell surface adhesion receptors play a central role in mediating cell migration. We have developed a model system consisting of CHO cells ectopically expressing the alpha IIb beta 3 integrin to study integrin affinity and cytoskeletal interactions during cell migration. The alpha IIb beta 3 integrins are suited for study of integrin receptors during cell migration because they are well characterized with respect to ligand binding, cytoskeletal interactions, and signal transduction, and mutants with altered receptor function are available. The alpha IIb beta 3 receptor specifically mediates migration of alpha IIb beta 3-transfected CHO cells. The migration of transfected CHO cells was studied on a fibrinogen substrate both by time lapse videomicroscopy and by random and haptotactic transwell assays. Haptotactic and random transwell assays measured distinct aspects of migration, with the random transwell assay correlating most closely with time lapse videomicroscopy. Mutations in the cytoplasmic domains that increase ligand affinity or activation of the alpha IIb beta 3 receptor into a high affinity state by the LIBS6 antibody decreased the migration rate. Likewise, mutations that increase cytoskeletal organization without affecting affinity also decreased the migration rate. In contrast, truncation of the beta chain, which alters cytoskeletal associations as assayed by absence of focal adhesions, decreased haptotactic migration while increasing random migration. These effects on the migration rate were partially compensated for by altering substrate concentration, demonstrating optimum substrate concentrations that supported maximal migration. For example, cells expressing integrins locked in the high affinity state showed maximal migration at lower substrate concentrations than cells expressing low affinity receptor. Together, these results implicate the strength of adhesion between cell and substrate, as modulated by receptor affinity, organization of adhesive complexes, and substrate concentration, as important regulators of cell migration rate. Further, we demonstrate a dominant effect of high affinity integrin in inhibiting migration regardless of the organization of adhesive complexes. These observations have potential implications for tumor metastasis and its therapy.
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DOI：
10.1083/jcb.130.2.441
发表时间：
1995-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Filardo EJ;Brooks PC;Deming SL;Damsky C;Cheresh DA
通讯作者：
Cheresh DA
影响因子：
3.7
作者：
BROWN, PJ;JULIANO, RL
通讯作者：
JULIANO, RL
影响因子：
2.2
作者：
LANDEGREN, U
通讯作者：
LANDEGREN, U
DOI：
10.1083/jcb.109.2.799
发表时间：
1989-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goodman SL;Risse G;von der Mark K
通讯作者：
von der Mark K
影响因子：
7.8
作者：
LEE, J;LEONARD, M;JACOBSON, K
通讯作者：
JACOBSON, K