title: Isthmin exerts pro-survival and death-promoting effect on endothelial cells through alphavbeta5 integrin depending on its physical state.
abstract: 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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Block S2, Science Drive 4, Singapore 117543, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Venugopal
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: W
authors.initials: W
authors.lastname: Xiang
authors.forename: Y-H
authors.initials: YH
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.forename: R M
authors.initials: RM
authors.lastname: Kini
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chong
authors.forename: R
authors.initials: R
authors.lastname: Ge
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D055767:Immobilized Proteins / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding; D019030:Receptors, Vitronectin / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D055767:Immobilized Proteins; D019030:Receptors, Vitronectin; D025521:Tumor Suppressor Proteins; C064660:integrin alphaVbeta5; D020169:Caspases