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Polydom-deficient mice die immediately after birth due to defects in lymphatic vessel remodeling, but the mechanism involved is poorly understood. Here, we report that Polydom directly binds to Tie1, an orphan receptor in the Angiopoietin\u2013Tie axis, and facilitates migration of lymphatic endothelial cells (LECs) in a Tie1-dependent manner. Polydom-induced LEC migration is diminished by PI3K inhibitors but not by an ERK inhibitor, suggesting that the PI3K\/Akt signaling pathway is involved in Polydom-induced LEC migration. In line with this possibility, Akt phosphorylation in LECs is enhanced by Polydom although no significant Tie1 phosphorylation is induced by Polydom. LECs also exhibited nuclear exclusion of Foxo1, a signaling event downstream of Akt activation, which was impaired in Polydom-deficient mice. These findings indicate that Polydom is a physiological ligand for Tie1 and participates in lymphatic vessel development through activation of the PI3K\/Akt pathway.<\/jats:p>","DOI":"10.1083\/jcb.202208047","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T02:21:12Z","timestamp":1686018072000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Polydom\/SVEP1 binds to Tie1 and promotes migration of lymphatic endothelial cells"],"prefix":"10.1083","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8730-9494","authenticated-orcid":true,"given":"Ryoko","family":"Sato-Nishiuchi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Matrixome Research and Application, Institute for Protein Research, Osaka University 1 , Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6469-3584","authenticated-orcid":true,"given":"Masamichi","family":"Doiguchi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Matrixome Research and Application, Institute for Protein Research, Osaka University 1 , Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-8398","authenticated-orcid":true,"given":"Nanami","family":"Morooka","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Matrixome Research and Application, Institute for Protein Research, Osaka University 1 , Suita, Japan"},{"id":[{"id":"https:\/\/ror.org\/00ndx3g44","id-type":"ROR","asserted-by":"publisher"}],"name":"Hamamatsu University School of Medicine 2 Department of Medical Physiology, , Hamamatsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6433-1410","authenticated-orcid":true,"given":"Kiyotoshi","family":"Sekiguchi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Matrixome Research and Application, Institute for Protein Research, Osaka University 1 , Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"2023080915335380400_bib1","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.devcel.2009.06.017","article-title":"Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis","volume":"17","author":"Bazigou","year":"2009","journal-title":"Dev. 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