Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans
Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans
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DOI：
10.1074/jbc.m003040200
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发表时间：
2000-08-11
影响因子：
4.8
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Chen, NY;Chen, CC;Lau, LF
血管生成诱导剂Cyr61是一种细胞外基质相关的肝素结合蛋白，可在培养的成纤维细胞和内皮细胞中介导细胞、黏附、刺激细胞迁移和增强生长因子刺激的DNA合成。在体内，Cyr61可诱导血管新生，促进肿瘤生长。Cyr61是一个高度保守的分泌蛋白家族的原型成员，包括结缔组织生长因子、肾母细胞瘤过度表达、ELM-1/WISP-1、Cop-1/WSAP-2和WISP-3。Cyr61由即刻早期基因编码，在皮肤创伤愈合过程中由培养的成纤维细胞和真皮成纤维细胞中的血清生长因子诱导合成。我们先前证实，Cyr61分别通过与整合素α(V)、β(3)和α(IIb)β(3)直接相互作用，介导血管内皮细胞的黏附和血小板的活化依赖性黏附。在这项研究中，我们发现原代人皮肤成纤维细胞对Cyr61的黏附是通过整合素α(6)β(1)和细胞表面硫酸乙酰肝素蛋白多糖(HSPGs)介导的，这两种物质最有可能作为辅助受体。细胞表面HSPG的破坏或Cyr61肝素结合位点的预先占据均可完全阻断细胞与Cyr61的黏附。Cyr61的肝素结合缺陷突变体不能通过整合素α(6)β(1)介导成纤维细胞的黏附，但仍能通过整合素α(V)β(3)介导内皮细胞黏附，这表明通过整合素α(V)β(3)的内皮细胞黏附不依赖于Cyr61的肝素结合活性。这些结果确认Cyr61是整合素α(6)β(1)的一种新的粘附性底物，并首次证明了在整合素介导的细胞附着中对HSPGs的需求。此外，这些发现表明，Cyr61可能通过与不同的整合素受体相互作用，在不同类型的细胞中产生不同的生物学效应。
The angiogenic inducer Cyr61 is an extracellular matrix-associated heparin-binding protein that can mediate cell, adhesion, stimulate cell migration, and enhance growth factor-stimulated DNA synthesis in both fibroblasts and endothelial cells in culture. In vivo, Cyr61 induces neovascularization and promotes tumor growth. Cyr61 is a prototypic member of a highly conserved family of secreted proteins that includes connective tissue growth factor, nephroblastoma overexpressed, Elm-1/WISP-1, Cop-1/WISP-2, and WISP-3. Encoded by an immediate early gene, Cyr61 synthesis is induced by serum growth factors in cultured fibroblasts and in dermal fibroblasts during cutaneous wound healing. We previously demonstrated that Cyr61 mediates adhesion of vascular endothelial cells and activation-dependent adhesion of blood platelets through direct interaction with integrins alpha(V)beta(3) and alpha(IIb)beta(3), respectively. In this study, we show that the adhesion of primary human skin fibroblasts to Cyr61 is mediated through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans (HSPGs), which most likely serve as co-receptors. Either destruction of cell surface HSPGs or prior occupancy of the Cyr61 heparin-binding site completely blocked cell adhesion to Cyr61. A heparin-binding defective mutant of Cyr61 was unable to mediate fibroblast adhesion through integrin alpha(6)beta(1) but still mediated endothelial cell adhesion through integrin alpha(V)beta(3) indicating that endothelial cell adhesion through integrin alpha(V)beta(3) is independent of the heparin-binding activity of Cyr61. These results identify Cyr61 as a novel adhesive substrate for integrin alpha(6)beta(1) and provide the first demonstration of the requirement for HSPGs in integrin-mediated cell attachment. In addition, these findings suggest that Cyr61 might elicit disparate biological effects in different cell types through interaction with distinct integrin receptors.