Abstract
Recently, we demonstrated in cultured endothelial cells and in vivo that deficiency of an isoform of intersectin-1, ITSN-1s, impairs caveolae and clathrin-mediated endocytosis and functionally upregulates compensatory pathways and their morphological carriers (i.e. enlarged endocytic structures, membranous rings or tubules) that are normally underrepresented. We now show that these endocytic structures internalize the broadly expressed transforming growth factor β receptor I (TGFβ-RI or TGFBR1), also known as Alk5, leading to its ubiquitylation and degradation. Moreover, the apoptotic or activated vascular cells of the ITSN-1s-knockdown mice release Alk5-bearing microparticles to the systemic circulation. These interact with and transfer Alk5 to endocytosis-deficient endothelial cells, resulting in lung endothelial cell survival and phenotypic alteration towards proliferation through activation of Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively). We also show that non-productive assembly of the Alk5–Smad–SARA (Smad anchor for receptor activation, also known as ZFYVE9) signaling complex and preferential formation of the Alk5–mSos–Grb2 complex account for Erk1/2 activation downstream of Alk5 and proliferation of pulmonary endothelial cells. Taken together, our studies demonstrate a functional relationship between the intercellular transfer of Alk5 by microparticles and endothelial cell survival and proliferation, and define a novel molecular mechanism for TGFβ and Alk5-dependent Erk1/2MAPK signaling that is significant for proliferative signaling and abnormal growth.
Highlights
Acute lung injury (ALI) or mild acute respiratory distress syndrome (ARDS), according to the Berlin definition (Ranieri et al, 2012) are associated with excessive endothelial and epithelial cells apoptosis (Henson and Tuder, 2008; Le et al, 2008; Predescu et al, 2013)
We have recently shown that in vivo deficiency of ITSN-1s, a highly prevalent protein of lung endothelium whose deficiency is relevant for the pathology of ALI/ARDS (Bardita et al, 2013; Predescu et al, 2013), induces extensive lung EC apoptosis and injury; after only 7 days of KD-ITSN, the remaining ECs exhibited phenotypic changes including hyperproliferation and apoptosisresistance against ITSN-1s deficiency, leading to increased microvessel density, repair and remodeling of the injured lung
We investigated the in vivo effects of long-term ITSN-1s deficiency on pulmonary vasculature and lung homeostasis, using a KD-ITSN mouse model generated by repeated delivery of a specific siRNA targeting ITSN-1 [siRNAIT SN ; (Bardita et al, 2013; Predescu et al, 2012)]
Summary
Acute lung injury (ALI) or mild acute respiratory distress syndrome (ARDS), according to the Berlin definition (Ranieri et al, 2012) are associated with excessive endothelial and epithelial cells apoptosis (Henson and Tuder, 2008; Le et al, 2008; Predescu et al, 2013). While apoptosis may induce pulmonary endothelial and epithelial barrier dysfunction leading to pulmonary edema, evidence suggests that apoptosis plays a beneficial role during ALI resolution due to the pro-regenerative role of clearance of apoptotic cells (Predescu et al, 2013; Schmidt and Tuder, 2010). This effect is mediated via the production of growth factors including TGFβ by macrophages engulfing apoptotic cells or perhaps by other vascular cells (Bardita et al, 2013; Henson and Tuder, 2008).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
