{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T07:00:10Z","timestamp":1785394810196,"version":"3.55.0"},"reference-count":0,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"U.S. Department of Defense","award":["W81XWH2110652"],"award-info":[{"award-number":["W81XWH2110652"]}]},{"name":"U.S. Department of Defense","award":["W81XWH2110518"],"award-info":[{"award-number":["W81XWH2110518"]}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["1R01HL176788-01"],"award-info":[{"award-number":["1R01HL176788-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Complex lymphatic anomalies (CLAs) are rare diseases characterized by the abnormal development of lymphatic vessels. CLAs can be caused by somatic activating mutations in KRAS (e.g., KrasG12D), which stimulate MAPK and PI3K signaling. While KRAS\/MAPK signaling is known to play a critical role in CLA pathogenesis, the contribution of KRAS\/PI3K\u03b1 signaling remains unclear. To investigate the role of RAS-activation of PI3K\u03b1 in CLAs, we analyzed mice carrying two missense mutations in the RAS-binding domain of p110\u03b1, the catalytic subunit of PI3K\u03b1. These two mutations block the interaction between p110\u03b1 and RAS but do not affect its kinase activity. Disruption of RAS-mediated PI3K\u03b1 activation in lymphatic endothelial cells reduced lymphatic vessel branching but did not affect lymphatic valve formation. In KrasG12D mutant mice, blocking RAS activation of p110\u03b1 reduced the pathological enlargement of lymphatic vessels, but failed to prevent KrasG12D-induced lymphatic valve loss. Similar results were observed following p110\u03b1 deletion in KrasG12D mutant mice. Together, these findings demonstrate that KrasG12D drives distinct disease phenotypes through separate downstream pathways. KRAS\/PI3K\u03b1 signaling promotes pathological lymphatic vessel enlargement, whereas KRAS\/MAPK signaling disrupts lymphatic valve formation.<\/jats:p>","DOI":"10.1242\/dmm.052932","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:25:42Z","timestamp":1785392742000},"source":"Crossref","is-referenced-by-count":0,"title":["Binding of RAS to PI3K\u03b1 regulates developmental and KRASG12D-induced lymphangiogenesis"],"prefix":"10.1242","author":[{"given":"Lorenzo M.","family":"Fernandes","sequence":"first","affiliation":[{"name":"1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Tresemer","sequence":"additional","affiliation":[{"name":"1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Vallejo","sequence":"additional","affiliation":[{"name":"1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Yao","sequence":"additional","affiliation":[{"name":"1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua P.","family":"Scallan","sequence":"additional","affiliation":[{"name":"2 Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-4239","authenticated-orcid":false,"given":"Michael T.","family":"Dellinger","sequence":"additional","affiliation":[{"name":"1 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA"},{"name":"3 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,7,30]]},"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052932\/3710746\/dmm052932.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.052932\/3710746\/dmm052932.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:25:43Z","timestamp":1785392743000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.052932\/372426\/Binding-of-RAS-to-PI3K-regulates-developmental-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1242\/dmm.052932","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"article-number":"dmm.052932"}}