Horowitz, Arie

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Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Cancer Biology Faculty Papers Department of Cancer Biology3-3-2017Letter by Horowitz Regarding Article, "ProteinInteractions at Endothelial Junctions and SignalingMechanisms Regulating Endothelial Permeability".Arie HorowitzThomas Jefferson University, arie.horowitz@jefferson.eduLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/cbfpPart of the Medicine and Health Sciences CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Cancer Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact:JeffersonDigitalCommons@jefferson.edu.Recommended CitationHorowitz, Arie, "Letter by Horowitz Regarding Article, "Protein Interactions at EndothelialJunctions and Signaling Mechanisms Regulating Endothelial Permeability"." (2017). Department ofCancer Biology Faculty Papers. Paper 113.https://jdc.jefferson.edu/cbfp/113Letter by Horowitz Regarding Article, “Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability”  To the Editor: The recent review by Komarova et al1 on Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability addresses a central topic in vascular biology that plays an important role in diabetes mellitus, cancer, and other common disorders. However, several statements in the review overlook evidence that does not support the views they promote:   1.Adherens junctions are presented as the “gatekeeper of the endothelial barrier,” practically the only junction that is acutely responsive to external stimuli by undergoing turnover. This statement promotes a common but erroneous assumption in the field. Ultrastructural studies had shown that tight junctions are pervasive not only in the brain and retina but also in the aorta and mesenteric artery (reference 40 in the review by Simionescu et al 2) and in the capillaries of the myocardium3,4 and the lung,5,6 to name a few. Similarly, there is ample evidence for tight junction turnover in response to agonists, including vascular endothelial growth factor (VEGF).7,8   2. The review assigns solely a junction-disassembly function to RhoA. Although this is a widely-held perception, it is simplistic—RhoA participates in both the maintenance and disassembly of cell junctions. At least in part, this depends on the RhoA effector: activation of Dia promotes junction stabilization, whereas activation of Rho-associated kinase triggers junction disassembly.9 This lapse applies also to the spatial control of Rho GTPase activity, where it is stated that RhoA is suppressed at endothelial adherens junctions. We had shown this is not always the case.4   3. Figure 2 presents the premise that nonmuscle myosin II unfolds (undergoes 10S–6S transition) on activation. This premise had been the subject of a long-lasting debate in the smooth muscle field but was shown conclusively to be incorrect.10 Nonmuscle myosin is highly homologous to smooth muscle myosin. As far as I know, the folded myosin conformation has never been detected in either nonmuscle or smooth muscle cells, although a monoclonal antibody specific to this conformation has been available.11  4. The review states that angiopoietin-1 inhibits VEGFR2 by uncoupling Src from the receptor, based on an irrelevant reference (reference 179 in the review by Whittard and Akiyama 12), while overlooking  evidence  showing  that  Src inhibition by angiopoietin-1 is mediated through the sequestration of the kinase away from VEGFR2 by Dia.13  Disclosures None.  Arie Horowitz Cardeza Center for Vascular Biology Departments of Medicine and Cancer Biology Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, PA  References 1. Komarova YA, Kruse K, Mehta D, Malik AB. Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability. Circ Res. 2017;120:179–206. doi: 10.1161/CIRCRESAHA.116.306534. 2. Simionescu M, Simionescu N, Palade GE. Segmental differentiations of cell junctions in the vascular endothelium. Arteries and veins. J Cell Biol. 1976;68:705-723. 3. Li Z, Jin ZQ. Ischemic preconditioning enhances integrity of coronary endothelial tight junctions. Biochem Biophys Res Commun. 2012;425:630–635. doi: 10.1016/j.bbrc.2012.07.130. 4. Ngok SP, Geyer R, Liu M, Kourtidis A, Agrawal S, Wu C, Seerapu HR, Lewis-Tuffin LJ, Moodie KL, Huveldt D, Marx R, Baraban JM, Storz P, Horowitz A, Anastasiadis PZ. VEGF and angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx. J Cell Biol. 2012;199:1103–1115. doi: 10.1083/jcb.201207009. 5. Morita K, Sasaki H, Furuse M, Tsukita S. Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol. 1999;147:185–194. 6. Walker DC, MacKenzie A, Hosford S. The structure of the tricellular region of endothelial tight junctions of pulmonary capillaries analyzed by freeze-fracture. Microvasc Res. 1994;48:259–281. doi: 10.1006/mvre.1994.1054. 7. Murakami T, Felinski EA, Antonetti DA. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem. 2009;284:21036–21046. doi: 10.1074/jbc.M109.016766. 8. Stamatovic SM, Keep RF, Wang MM, Jankovic I, Andjelkovic AV. Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells. J Biol Chem. 2009;284:19053–19066. doi: 10.1074/jbc.M109.000521. 9. Sahai E, Marshall CJ. ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol. 2002;4:408–415. doi: 10.1038/ncb796. 10. Horowitz A, Trybus KM, Bowman DS, Fay FS. Antibodies probe for folded monomeric myosin in relaxed and contracted smooth muscle. J Cell Biol. 1994;126:1195–1200. 11. Trybus KM, Henry L. Monoclonal antibodies detect and stabilize conformational states of smooth muscle myosin. J Cell Biol. 1989;109:2879–2886. 12. Whittard JD, Akiyama SK. Positive regulation of cell-cell and cell-substrate adhesion by protein kinase A. J Cell Sci. 2001;114:3265–3272. 13. Gavard J, Patel V, Gutkind JS. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell. 2008;14:25–36. doi: 10.1016/j.devcel.2007.10.019   

Letter by Horowitz Regarding Article,  Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability .

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Letter by Horowitz Regarding Article, Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability .

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