Coordinate role for cell surface chondroitin sulfate proteoglycan and alpha 4 beta 1 integrin in mediating melanoma cell adhesion to fibronectin.
Coordinate role for cell surface chondroitin sulfate proteoglycan and alpha 4 beta 1 integrin in mediating melanoma cell adhesion to fibronectin.
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DOI：
10.1083/jcb.118.2.431
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发表时间：
1992-07
期刊：
影响因子：
--
通讯作者：
McCarthy JB
中科院分区：
文献类型：
--
作者：
Iida J;Skubitz AP;Furcht LT;Wayner EA;McCarthy JB
细胞对细胞外基质（ECM）的识别和粘附具有复杂的分子基础，涉及整合素和细胞表面蛋白聚糖（PG）。目前的研究已经使用硫酸软骨素蛋白聚糖（CSPG）合成的特异性抑制剂沿着抗α 4整联蛋白亚基单克隆抗体来证明人黑素瘤细胞与人血浆纤连蛋白（FN）的A链衍生的33-kD羧基末端肝素结合片段的粘附涉及细胞表面CSPG和α 4 β 1整联蛋白。细胞表面CSPG在介导黑色素瘤细胞粘附到该FN片段中的直接作用通过鉴定片段内的阳离子合成肽（称为FN-C/H-III）来证明。FN-C/H-III位于片段的氨基末端附近，代表完整FN的残基#1721-1736。FN-C/H-III直接结合CSPG，可抑制CSPG与片段的结合，并通过CSPG依赖性、α 4 β 1整合素非依赖性机制促进黑素瘤细胞粘附。FN-C/H-III的乱序形式不抑制CSPG与片段或FN-C/H-III的结合或细胞粘附，这表明FN-C/H-III的一级序列对其生物学性质是重要的。以前的研究已经确定了其他三个合成肽从这个33 kD的FN片段，促进细胞粘附的乙酰氨基甘氨酰天冬氨酸（RGD）的独立机制。这些合成肽中的两种（FN-C/H-I和FN-C/H-II）结合肝素并促进细胞粘附，暗示细胞表面PG介导这两种肽的细胞识别。此外，第三种合成肽CS 1位于FN-C/H-I和FN-C/H-II附近，它通过α 4 β 1整联蛋白依赖性机制促进细胞粘附。与FN-C/H-III相反，这三种肽的细胞识别涉及CSPG和α 4整联蛋白亚基的贡献。特别重要的是，观察表明，CS 1介导的黑色素瘤细胞粘附可以通过干扰CSPG合成或表达来抑制。由于CS 1不结合CSPG，因此结果表明CSPG可能改变人黑素瘤细胞表面α 4 β 1整联蛋白的功能和/或活性。总之，这些结果支持了一个模型，其中PG和整合素结合位点内的33 kD片段可能会采取一致行动，集中这两个细胞粘附受体到细胞表面上的紧密接近，从而影响初始的细胞识别事件，有助于黑色素瘤细胞粘附在这个片段。
Cellular recognition and adhesion to the extracellular matrix (ECM) has a complex molecular basis, involving both integrins and cell surface proteoglycans (PG). The current studies have used specific inhibitors of chondroitin sulfate proteoglycan (CSPG) synthesis along with anti- alpha 4 integrin subunit monoclonal antibodies to demonstrate that human melanoma cell adhesion to an A-chain derived, 33-kD carboxyl- terminal heparin binding fragment of human plasma fibronectin (FN) involves both cell surface CSPG and alpha 4 beta 1 integrin. A direct role for cell surface CSPG in mediating melanoma cell adhesion to this FN fragment was demonstrated by the identification of a cationic synthetic peptide, termed FN-C/H-III, within the fragment. FN-C/H-III is located close to the amino terminal end of the fragment, representing residues #1721-1736 of intact FN. FN-C/H-III binds CSPG directly, can inhibit CSPG binding to the fragment, and promotes melanoma cell adhesion by a CSPG-dependent, alpha 4 beta 1 integrin- independent mechanism. A scrambled version of FN-C/H-III does not inhibit CSPG binding or cell adhesion to the fragment or to FN-C/H-III, indicating that the primary sequence of FN-C/H-III is important for its biological properties. Previous studies have identified three other synthetic peptides from within this 33-kD FN fragment that promote cell adhesion by an arginyl-glycyl-aspartic acid (RGD) independent mechanism. Two of these synthetic peptides (FN-C/H-I and FN-C/H-II) bind heparin and promote cell adhesion, implicating cell surface PG in mediating cellular recognition of these two peptides. Additionally, a third synthetic peptide, CS1, is located in close proximity to FN-C/H-I and FN-C/H-II and it promotes cell adhesion by an alpha 4 beta 1 integrin-dependent mechanism. In contrast to FN-C/H-III, cellular recognition of these three peptides involved contributions from both CSPG and alpha 4 integrin subunits. Of particular importance are observations demonstrating that CS1-mediated melanoma cell adhesion could be inhibited by interfering with CSPG synthesis or expression. Since CS1 does not bind CSPG, the results suggest that CSPG may modify the function and/or activity of alpha 4 beta 1 integrin on the surface of human melanoma cells. Together, these results support a model in which the PG and integrin binding sites within the 33-kD fragment may act in concert to focus these two cell adhesion receptors into close proximity on the cell surface, thereby influencing initial cellular recognition events that contribute to melanoma cell adhesion on this fragment.