title: Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway.
abstract: Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin αvβ3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by αvβ3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting αvβ3 signaling, this collagen epitope promoted αvβ3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates αvβ3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control αvβ3 signaling by targeting a pro-angiogenic and inflammatory ligand of αvβ3 rather than the receptor itself.
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Ames
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Liangru
authors.initials: L
authors.lastname: Contois
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Caron
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Eric
authors.initials: E
authors.lastname: Tweedie
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Robert
authors.initials: R
authors.lastname: Friesel
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074.
authors.forename: Calvin
authors.initials: C
authors.lastname: Vary
authors.affiliation: From the Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, Maine 04074 brookp1@mmc.org.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Brooks
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D040542:Mechanotransduction, Cellular / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000939:Epitopes; D039302:Integrin alphaVbeta3; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D003094:Collagen; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Yes-associated protein (YAP); angiogenesis; collagen; extracellular matrix; inflammation; integrin; p38 MAPK