Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth.
Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth.
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DOI：
10.1083/jcb.139.1.279
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发表时间：
1997-10-06
期刊：
影响因子：
--
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
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作者：
Jones PL;Crack J;Rabinovitch M
腱生蛋白-C（TN-C）在肺血管疾病中被诱导，在那里它与增殖平滑肌细胞（SMC）和表皮生长因子（EGF）共定位。此外，培养的SMC需要TN-C用于I型胶原的EGF依赖性生长。本研究旨在探讨TN-C在平滑肌细胞中的调节和功能。我们发现基质金属蛋白酶（MMP）抑制剂（GM 6001）抑制SMC TN-C在天然胶原上的表达，而变性胶原以β3整合素依赖性方式促进TN-C表达，不依赖于MMP。在EGF存在下，漂浮型I型胶原凝胶还抑制SMC MMP活性和TN-C蛋白合成并诱导细胞凋亡。将外源性TN-C添加到漂浮胶原上的SMC或用GM 6001处理的SMC中，恢复EGF生长反应并“拯救”细胞免于凋亡。然后研究TN-C促进EGF依赖性存活和生长的机制。我们发现TN-C与αvβ3整合素的相互作用改变了SMC的形状和EGF依赖性生长。这些特征与丝状肌动蛋白重新分配至粘着斑复合物有关，粘着斑复合物与EGF-Rs簇、酪氨酸磷酸化蛋白共定位，并且添加EGF后EGF-Rs的激活增加。交联SMC β3整合素复制TN-C对EGF-R聚集和酪氨酸磷酸化的作用。总之，这些研究代表了ECM依赖性细胞存活的功能范例，其中MMP通过在I型胶原中产生β3整联蛋白配体上调TN-C。反过来，αvβ3与TN-C的相互作用改变了SMC的形状，增加了EGF-R聚集和EGF依赖性生长。相反，抑制MMPs下调TN-C并诱导细胞凋亡。
Tenascin-C (TN-C) is induced in pulmonary vascular disease, where it colocalizes with proliferating smooth muscle cells (SMCs) and epidermal growth factor (EGF). Furthermore, cultured SMCs require TN-C for EGF-dependent growth on type I collagen. In this study, we explore the regulation and function of TN-C in SMCs. We show that a matix metalloproteinase (MMP) inhibitor (GM6001) suppresses SMC TN-C expression on native collagen, whereas denatured collagen promotes TN-C expression in a β3 integrin– dependent manner, independent of MMPs. Floating type I collagen gel also suppresses SMC MMP activity and TN-C protein synthesis and induces apoptosis, in the presence of EGF. Addition of exogenous TN-C to SMCs on floating collagen, or to SMCs treated with GM6001, restores the EGF growth response and “rescues” cells from apoptosis. The mechanism by which TN-C facilitates EGF-dependent survival and growth was then investigated. We show that TN-C interactions with αvβ3 integrins modify SMC shape, and EGF- dependent growth. These features are associated with redistribution of filamentous actin to focal adhesion complexes, which colocalize with clusters of EGF-Rs, tyrosine-phosphorylated proteins, and increased activation of EGF-Rs after addition of EGF. Cross-linking SMC β3 integrins replicates the effect of TN-C on EGF-R clustering and tyrosine phosphorylation. Together, these studies represent a functional paradigm for ECM-dependent cell survival whereby MMPs upregulate TN-C by generating β3 integrin ligands in type I collagen. In turn, αvβ3 interactions with TN-C alter SMC shape and increase EGF-R clustering and EGF-dependent growth. Conversely, suppression of MMPs downregulates TN-C and induces apoptosis.