Pulmonary pericytes regulate lung morphogenesis

Blood vessels are essential for blood circulation but also control organ growth, homeostasis, and regeneration, which has been attributed to the release of paracrine signals by endothelial cells. Endothelial tubules are associated with specialised mesenchymal cells, termed pericytes, which help to maintain vessel wall integrity. Here we identify pericytes as regulators of epithelial and endothelial morphogenesis in postnatal lung. Mice lacking expression of the Hippo pathway components YAP and TAZ in pericytes show defective alveologenesis. Mutant pericytes are present in normal numbers but display strongly reduced expression of hepatocyte growth factor leading to impaired activation of the c-Met receptor, which is expressed by alveolar epithelial cells. YAP and TAZ are also required for expression of angiopoietin-1 by pulmonary pericytes, which also controls hepatocyte growth factor expression and thereby alveologenesis in an autocrine fashion. These findings establish that pericytes have important, organ-specific signalling properties and coordinate the behavior of epithelial and vascular cells during lung morphogenesis. © 2018 The Author(s

Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta 1 with higher affinity receptors and an activated Alk1 pathway

Endoglin is an accessory receptor for transforming growth factor beta (TGF beta ) in endothelial cells, essential for vascular development. Its pivotal role in angiogenesis is underscored in Endoglin null (Eng super(-/-)) murine embryos, which die at mid-gestation (E10.5) from impaired yolk sac vessel formation. Moreover, mutations in endoglin and the endothelial-specific TGF beta type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGF beta pathways, we derived murine endothelial cell lines from Eng super(+/+) and Eng super(-/-) embryos (E9.0). Whereas Eng super(+/+) cells were only partially growth inhibited by TGF beta , Eng super(-/-) cells displayed a potent anti-proliferative response. TGF beta -dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng super(-/-) cells. In contrast, TGF beta treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGF beta concentrations. Enhanced activity of the Smad1 pathway in Eng super(-/-) cells was reflected in higher expression of ALK1-dependent genes such as Id1, Smad6, and Smad7. Analysis of cell surface receptors revealed that the TGF beta type I receptor, ALK5, which is required for ALK1 function, was increased in Eng super(-/-) cells. TGF beta receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGF beta signaling in endothelial cells by regulating surface TGF beta receptors and suppressing Smad1 activation. Thus an altered balance in TGF beta receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis

Protein interaction network of the mammalian hippo pathway reveals mechanisms of kinase-phosphatase interactions

10.1126/scisignal.2004712Science Signaling6302rs15

Transforming Growth Factor-β Receptors Interact with AP2 by Direct Binding to β2 Subunit

Transforming growth factor-β (TGF-β) superfamily members regulate a wide range of biological processes by binding to two transmembrane serine/threonine kinase receptors, type I and type II. We have previously shown that the internalization of these receptors is inhibited by K(+) depletion, cytosol acidification, or hypertonic medium, suggesting the involvement of clathrin-coated pits. However, the involvement of the clathrin-associated adaptor complex AP2 and the identity of the AP2 subunit that binds the receptors were not known. Herein, we have studied these issues by combining studies on intact cells with in vitro assays. Using fluorescence photobleaching recovery to measure the lateral mobility of the receptors on live cells (untreated or treated to alter their coated pit structure), we demonstrated that their mobility is restricted by interactions with coated pits. These interactions were transient and mediated through the receptors' cytoplasmic tails. To measure direct binding of the receptors to specific AP2 subunits, we used yeast two-hybrid screens and in vitro biochemical assays. In contrast to most other plasma membrane receptors that bind to AP2 via the μ2 subunit, AP2/TGF-β receptor binding was mediated by a direct interaction between the β2-adaptin N-terminal trunk domain and the cytoplasmic tails of the receptors; no binding was observed to the μ2, α, or ς2 subunits of AP2 or to μ1 of AP1. The data uniquely demonstrate both in vivo and in vitro the ability of β2-adaptin to directly couple TGF-β receptors to AP2 and to clathrin-coated pits, providing the first in vivo evidence for interactions of a transmembrane receptor with β2-adaptin