CELLULAR INTERACTIONS WITH THROMBOSPONDIN

我们的目标是了解黏附蛋白的作用 凝血酶敏感蛋白调节肿瘤细胞黏附、生长、运动 和转移。就像许多粘附性蛋白质一样， 凝血酶敏感蛋白具有与几种基质成分的结合部位和 结合几种类型的细胞表面受体。我们已经证明了 凝血酶反应蛋白促进黑色素瘤的黏附和迁移 其他肿瘤细胞系，并调节细胞的迁移和增殖 内皮细胞。我们发现至少有两个域 这些活动需要凝血酶敏感蛋白，而且 凝血酶敏感蛋白与蛋白质和硫酸糖偶联物的相互作用 细胞膜上的受体。使用合成肽和重组 片段，我们已经确定了三个功能位点，其中包括一本小说 凝血酶原蛋白I型重复序列中的黏附序列 整个分子调节细胞黏附的活动， 迁徙和扩散。最近我们也发现了 凝血酶反应蛋白中激活潜伏的转化生长因子-β或 通过完整的凝血酶原蛋白抑制其激活。这些多肽具有 癌症和其他疾病的潜在临床应用 与异常血管生成和调节伤口修复有关， 炎症反应和纤维化。 我们正在开发了解分子的实验方法 细胞与凝血酶反应蛋白多重相互作用的机制 以及它们所引发的细胞反应。我们感兴趣的是 凝血酶反应蛋白表达对肿瘤细胞的直接影响作用 凝血酶敏感蛋白在肿瘤新生血管形成中的作用 其他肿瘤细胞在转移过程中与内皮细胞相互作用。

Our objective is to understand the role of the adhesive protein thrombospondin in regulating tumor cell adhesion, growth, motility, and metastasis. As is the case for many adhesive proteins, thrombospondin has binding sites for several matrix components and binds to several types of cell surface receptors. We have shown that thrombospondin promotes adhesion and migration of melanoma and several other tumor cell lines and modulates migration and proliferation of endothelial cells. We found that at least two domains of thrombospondin are required for these activities and that thrombospondin interacts with both protein and sulfated glycoconjugate receptors on cell membranes. Using synthetic peptides and recombinant fragments, we have identified three functional sites including a novel adhesive sequence in the type I repeats of thrombospondin that mimics the activities of the whole molecule for regulating cell adhesion, migration and proliferation. Recently, we have also identified specific sequences in thrombospondin that activate latent TGF-beta or inhibit its activation by intact thrombospondin. These peptides have potential clinical applications in cancer and other diseases associated with abnormal angiogenesis and in regulating wound repair, inflammatory responses, and fibrosis. We are developing experimental approaches to understand the molecular mechanisms of these multiple interactions of cells with thrombospondin and the cellular responses they elicit. We are interested in the direct effects of thrombospondin expression on tumor cells, the role of thrombospondin in neovascularization of tumors, and its role in other tumor cell interactions with endothelium during metastasis.