Department of Biological Sciences, National University of Singapore, Block S2, Science Drive 4, Singapore 117543, Singapore.
Cell Death Dis. 2011 May 5;2(5):e153. doi: 10.1038/cddis.2011.37.
Isthmin (ISM) is a 60 kDa secreted-angiogenesis inhibitor that suppresses tumor growth in mouse and disrupts vessel patterning in zebrafish embryos. It selectively binds to alphavbeta5 (αvβ5) integrin on the surface of endothelial cells (ECs), but the mechanism of its antiangiogenic action remains unknown. In this work, we establish that soluble ISM suppresses in vitro angiogenesis and induces EC apoptosis by interacting with its cell surface receptor αvβ5 integrin through a novel 'RKD' motif localized within its adhesion-associated domain in MUC4 and other proteins domain. ISM induces EC apoptosis through integrin-mediated death (IMD) by direct recruitment and activation of caspase-8 without causing anoikis. On the other hand, immobilized ISM loses its antiangiogenic function and instead promotes EC adhesion, survival and migration through αvβ5 integrin by activating focal adhesion kinase (FAK). ISM unexpectedly has both a pro-survival and death-promoting effect on ECs depending on its physical state. This dual function of a single antiangiogenic protein may impact its antiangiogenic efficacy in vivo.
Isthmin（ISM）是一种 60kDa 的分泌型血管生成抑制剂，可抑制小鼠肿瘤生长，并破坏斑马鱼胚胎中的血管模式。它选择性地结合到内皮细胞（EC）表面的αvβ5 整联蛋白，但它的抗血管生成作用机制尚不清楚。在这项工作中，我们通过位于黏附相关域中的新型“RKD”基序，证实可溶性 ISM 通过与细胞表面受体αvβ5 整联蛋白相互作用，从而抑制体外血管生成并诱导 EC 凋亡，该黏附相关域存在于 MUC4 和其他蛋白域中。ISM 通过直接募集和激活 caspase-8 诱导 EC 凋亡，而不会引起失巢凋亡。另一方面，固定化的 ISM 通过激活粘着斑激酶（FAK），通过 αvβ5 整联蛋白丧失其抗血管生成功能，反而促进 EC 黏附、存活和迁移。出乎意料的是，ISM 对 EC 具有促生存和促进死亡的双重作用，这取决于其物理状态。这种单一抗血管生成蛋白的双重功能可能会影响其在体内的抗血管生成效果。
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