{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:34:33Z","timestamp":1781102073520,"version":"3.54.1"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,6,19]]},"abstract":"<jats:p>\n                    The anthrax lethal toxin (LT) enters host cells and enzymatically cleaves MAPKKs or MEKs. How these molecular events lead to death from anthrax remains poorly understood, but published reports suggest a direct effect of LT on vascular permeability. We have found that LT challenge in mice disrupts signaling through Tie-2, a tonically activated receptor tyrosine kinase in the endothelium. Genetic manipulations favoring Tie-2 activation enhanced interendothelial junctional contacts, prevented vascular leakage, and promoted survival following a lethal dose of LT. Cleavage of MEK1\/2 was necessary for LT to induce endothelial barrier dysfunction, and activated Tie-2 signaled through the uncleaved fraction of MEKs to prevent LT\u2019s effects on the endothelium. Finally, primates infected with toxin-secreting\n                    <jats:italic>Bacillus anthracis<\/jats:italic>\n                    bacilli developed a rapid and marked imbalance in the endogenous ligands that signal Tie-2, similar to that seen in LT-challenged mice. Our results show that\n                    <jats:italic>B. anthracis<\/jats:italic>\n                    LT blunts signaling through Tie-2, thereby weakening the vascular barrier and contributing to lethality of the disease. Measurement of circulating Tie-2 ligands and manipulation of Tie-2 activity may represent future prognostic and therapeutic avenues for humans exposed to\n                    <jats:italic>B. anthracis<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.1120755109","type":"journal-article","created":{"date-parts":[[2012,6,5]],"date-time":"2012-06-05T10:05:21Z","timestamp":1338890721000},"page":"10024-10029","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":53,"title":["Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax"],"prefix":"10.1073","volume":"109","author":[{"given":"Chandra C.","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215;"},{"name":"Harvard Medical School, Boston, MA 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