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p18 Regulates Tubulogenesis in the Pulmonary Endothelium Through p38/mTOR‐dependent Pathway
Author(s) -
Chichger Havovi,
Braza Julie,
Duong Huetran,
Stark Myranda,
Harrington Elizabeth
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.630.12
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , endosome , mapk/erk pathway , chemistry , angiogenesis , vasculogenesis , endocytic cycle , endothelium , biology , endocytosis , signal transduction , cancer research , progenitor cell , cell , biochemistry , intracellular , stem cell , endocrinology
Vasculogenesis and angiogenesis, the formation of new blood vessels, are processes requiring multiple endothelial cell (EC) functions, including proliferation, migration and adhesion. Blood vessel lumen formation is necessary for the creation of a functional vessel to transport blood, fluids, and nutrients and occurs via tubulogenesis. This process of lumen formation is not completely understood, however there is evidence for the role of the endosome. The endosomal adaptor protein p18 anchors the late endosome/lysosome to facilitate mTOR/MAPK activation. We have demonstrated that p18 binds to the early endosome to enhance VE‐cadherin recycling to EC junctions and improve EC barrier function via an mTOR/MAPK independent pathway. As EC permeability is a key component of tubulogenesis, we hypothesize that p18 localized to the endosome regulates tubulogenesis in the pulmonary EC, potentially through regulation of MAPK and mTOR activity. Lung EC were transfected with cDNA encoding p18 wt display significantly increased EC migration, adhesion to gelatin and in vitro and in vivo tube formation, but had no effect of proliferation. Inhibition of mTOR (rapamycin) or p38MAPK (SB203580) significantly attenuated the pro‐tubulogenic role of p18 wt . Conversely, overexpression of the non‐endosomal binding p18 (p18 N39 ) and p18 siRNA knockdown attenuated VEGF‐induced adhesion and proliferation. Thus our data demonstrates a key role for endocytic protein p18 in promoting tubulogenesis within the pulmonary vasculature through activation of mTOR and p38. Thus we implicate p18 as a novel therapeutic target to regulate vessel formation within the pulmonary vasculature.