Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium.

Activation of Hedgehog (Hh) signaling requires the transmembrane protein Smoothened (Smo), a member of the G-protein coupled receptor superfamily. In mammals, Smo translocates to the primary cilium upon binding of Hh ligands to their receptor, Patched (Ptch1), but it is unclear if ciliary trafficking of Smo is sufficient for pathway activation. Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of Smo, force ciliary translocation of Smo. Treatment with SANT-1, an unrelated Smo antagonist, abrogates cyclopamine- and jervine-mediated Smo translocation. Further, activation of protein kinase A, either directly or through activation of Galphas, causes Smo to translocate to a proximal region of the primary cilium. We propose that Smo adopts multiple inactive and active conformations, which influence its localization and trafficking on the primary cilium

A mammalian Wnt5a-Ror2-Vangl2 axis controls the cytoskeleton and confers cellular properties required for alveologenesis.

Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in alveolar epithelial cells and myofibroblasts for alveologenesis in mammals. Our studies uncovered a Wnt5a-Ror2-Vangl2 cascade that endows cellular properties and novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior

Immunoprevention of Basal Cell Carcinomas with Recombinant Hedgehog-interacting Protein

Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly overexpress several hedgehog target genes. We report here our use of one of these target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen for immunoprevention of BCCs in Ptch1+/− mice treated with ionizing radiation. Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than those in BCCs. Immunization with either of two large recombinant Hip1 polypeptides was well tolerated in Ptch1+/− mice, induced B and T cell responses detectable by enzyme-linked immunosorbent assay, Western blot, delayed type hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively. We conclude that immunization with proteins specifically up-regulated by hedgehog signaling may hold promise as a preventive option for patients such as those with the basal cell nevus syndrome who are destined to develop large numbers of BCCs

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities

Hedgehog signaling: From basic research to clinical applications

Studies of the major signaling pathways have revealed a connection between development, regeneration, and cancer, highlighting common signaling networks in these processes. The Hedgehog (Hh) pathway plays a central role in the development of most tissues and organs in mammals. Hh signaling is also required for tissue homeostasis and regeneration in adults, while perturbed Hh signaling is associated with human cancers. A fundamental understanding of Hh signaling will not only enhance our knowledge of how the embryos are patterned but also provide tools to treat diseases related to aberrant Hh signaling. Studies have yielded a basic framework of Hh signaling, which establishes the foundation for addressing unresolved issues of Hh signaling. A detailed characterization of the biochemical interactions between Hh components will help explain the production of graded Hh responses required for tissue patterning. Additional cell biological and genetic studies will offer new insight into the role of Hh signaling in homeostasis and regeneration. Finally, drugs that are capable of manipulating the Hh pathway can be used to treat human diseases caused by disrupted Hh signaling. These investigations will serve as a paradigm for studying signal transduction/integration in homeostasis and disease, and for translating discovery from bench to bedside

New “hogs” in Hedgehog transport and signal reception

et al., 2006; Zhang et al., 2006) identify a new receptor component for Hedgehog, a key morphogen in embryonic development. Many other proteins that bind to Hedgehog in the extracellular matrix or on the cell surface have been identified. In light of these recent discoveries, we discuss how these factors control the stability, transport, reception, and availability of Hedgehog in modulating Hedgehog-mediated responses

A conserved MST1/2–YAP axis mediates Hippo signaling during lung growth

Hippo signaling is a critical player in controlling the growth of several tissues and organs in diverse species. The current model of Hippo signaling postulates a cascade of kinase activity initiated by the MST1/2 kinases in response to external stimuli. This leads to inactivation of the transcriptional coactivators, YAP/TAZ, due to their cytoplasmic retention and degradation that is correlated with YAP/TAZ phosphorylation. In most tissues examined, YAP plays a more dominant role than TAZ. Whether a conserved Hippo pathway is utilized during lung growth and development is unclear. In particular, the regulatory relationship between MST1/2 and YAP/TAZ in the lung remains controversial. By employing the Shh-Cre mouse line to efficiently inactivate genes in the lung epithelium, we show that loss of MST1/2 kinases in the epithelium can lead to neonatal lethality caused by lung defects. This is manifested by perturbation of lung epithelial cell proliferation and differentiation. These phenotypes are more severe than those produced by Nkx2.1-Cre, highlighting the effects of differential Cre activity on phenotypic outcomes. Importantly, expression of YAP targets is upregulated and the ratio of phospho-YAP to total YAP protein levels is reduced in Mst1/2-deficient lungs, all of which are consistent with a negative role of MST1/2 in controlling YAP function. This model gains further support from both in vivo and in vitro studies. Genetic removal of one allele of Yap or one copy of both Yap and Taz rescues neonatal lethality and lung phenotypes due to loss of Mst1/2. Moreover, knockdown of Yap in lung epithelial cell lines restores diminished alveolar marker expression caused by Mst1/2 inactivation. These results demonstrate that MST1/2 inhibit YAP/TAZ activity and establish a conserved MST1/2-YAP axis in coordinating lung growth during development

Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung

Hedgehog (Hh) signaling plays a major role in multiple aspects of embryonic development. A key issue is how negative regulation of Hh signaling might contribute to generating differential responses over tens of cell diameters. In cells that respond to Hh, two proteins that are up-regulated are Patched1 (Ptch1), the Hh receptor, a general target in both invertebrate and vertebrate organisms, and Hip1, a Hh-binding protein that is vertebrate specific. To address the developmental role of Hip1 in the context of Hh signaling, we generated Hip1 mutants in the mouse. Loss of Hip1 function results in specific defects in two Hh target issues, the lung, a target of Sonic hedgehog (Shh) signaling, and the endochondral skeleton, a target of Indian hedgehog (Ihh) signaling. Hh signaling was up-regulated in Hip1 mutants, substantiating Hip1's general role in negatively regulating Hh signaling. Our studies focused on Hip1 in the lung. Here, a dynamic interaction between Hh and fibroblast growth factor (Fgf) signaling, modulated at least in part by Hip1, controls early lung branching