scholarly journals Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating Hedgehog signaling

2011 ◽  
Vol 192 (4) ◽  
pp. 691-704 ◽  
Author(s):  
Fuchuan Li ◽  
Wen Shi ◽  
Mariana Capurro ◽  
Jorge Filmus
Keyword(s):  
Cell Proliferation ◽  
Heparan Sulfate ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Core Protein ◽  
Stimulatory Activity ◽  
Rhabdomyosarcoma Cell ◽  
Hh Signaling ◽  
Patched 1

Glypican-5 (GPC5) is one of the six members of the glypican family. It has been previously reported that GPC5 stimulates the proliferation of rhabdomyosarcoma cells. In this study, we show that this stimulatory activity of GPC5 is a result of its ability to promote Hedgehog (Hh) signaling. We have previously shown that GPC3, another member of the glypican family, inhibits Hh signaling by competing with Patched 1 (Ptc1) for Hh binding. Furthermore, we showed that GPC3 binds to Hh through its core protein but not to Ptc1. In this paper, we demonstrate that GPC5 increases the binding of Sonic Hh to Ptc1. We also show that GPC5 binds to both Hh and Ptc1 through its glycosaminoglycan chains and that, unlike GPC3, GPC5 localizes to the primary cilia. Interestingly, we found that the heparan sulfate chains of GPC5 display a significantly higher degree of sulfation than those of GPC3. Based on these results, we propose that GPC5 stimulates Hh signaling by facilitating/stabilizing the interaction between Hh and Ptc1.

scholarly journals Glypican-6 promotes the growth of developing long bones by stimulating Hedgehog signaling

2017 ◽  
Vol 216 (9) ◽  
pp. 2911-2926 ◽  
Author(s):  
Mariana Capurro ◽  
Tomomi Izumikawa ◽  
Philippe Suarez ◽  
Wen Shi ◽  
Marzena Cydzik ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Autosomal Recessive ◽  
Cultured Cells ◽  
Core Protein ◽  
Facial Dysmorphism ◽  
Long Bones ◽  
Loss Of Function ◽  
Genetic Condition ◽  
Hh Signaling ◽  
Patched 1

Autosomal-recessive omodysplasia (OMOD1) is a genetic condition characterized by short stature, shortened limbs, and facial dysmorphism. OMOD1 is caused by loss-of-function mutations of glypican 6 (GPC6). In this study, we show that GPC6-null embryos display most of the abnormalities found in OMOD1 patients and that Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos. The Hh-stimulatory activity of GPC6 was also observed in cultured cells, where this GPC increased the binding of Hh to Patched 1 (Ptc1). Consistent with this, GPC6 interacts with Hh through its core protein and with Ptc1 through its glycosaminoglycan chains. Hh signaling is triggered at the primary cilium. In the absence of Hh, we observed that GPC6 is localized outside of the cilium but moves into the cilium upon the addition of Hh. We conclude that GPC6 stimulates Hh signaling by binding to Hh and Ptc1 at the cilium and increasing the interaction of the receptor and ligand.

scholarly journals CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids

2021 ◽  
Author(s):  
Megan Lo ◽  
Amnon Sharir ◽  
Michael D Paul ◽  
Hayarpi Torosyan ◽  
Christopher Agnew ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Membrane Composition ◽  
Hh Signaling ◽  
Pathway Regulation ◽  
Patched 1 ◽  
Cancer Signal Transduction

The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can cause congenital malformations, such as digit anomalies and holoprosencephaly, and other diseases, including cancer. Signal transduction is initiated by HH ligand binding to the Patched 1 (PTCH1) receptor on primary cilia, thereby releasing inhibition of Smoothened (SMO), a HH pathway activator. Although cholesterol and several oxysterol lipids, which are enriched in the ciliary membrane, play a crucial role in HH activation, the molecular mechanisms governing the regulation of these lipid molecules remain unresolved. Here, we identify Canopy 4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that controls membrane sterol lipid levels. Cnpy4—/— embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway at the level of SMO in vitro, and elevates membrane levels of accessible sterol lipids such as cholesterol, an endogenous ligand involved in SMO activation. Thus, our data demonstrate that CNPY4 is a negative regulator that fine-tunes the initial steps of HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.

scholarly journals Roles of the Primary Cilium Component Polaris in Synchondrosis Development

2009 ◽  
Vol 88 (6) ◽  
pp. 545-550 ◽  
Author(s):  
T. Ochiai ◽  
M. Nagayama ◽  
T. Nakamura ◽  
T. Morrison ◽  
D. Pilchak ◽  
...  
Keyword(s):  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Cranial Base ◽  
Indian Hedgehog ◽  
Intramembranous Ossification ◽  
Endochondral Bone ◽  
Chondrocyte Maturation ◽  
Mouse Mutants ◽  
Patched 1

Primary cilia regulate several developmental processes and mediate hedgehog signaling. To study their roles in cranial base development, we created conditional mouse mutants deficient in Polaris, a critical primary cilium component, in cartilage. Mutant post-natal cranial bases were deformed, and their synchondrosis growth plates were disorganized. Expression of Indian hedgehog, Patched-1, collagen X, and MMP-13 was reduced and accompanied by decreases in endochondral bone. Interestingly, there was excessive intramembranous ossification along the perichondrium, accompanied by excessive Patched-1 expression, suggesting that Ihh distribution was wider and responsible for such excessive response. Indeed, expression of heparan sulfate proteoglycans (HS-PGs), normally involved in restricting hedgehog distribution, was barely detectable in mutant synchondroses. Analyses of the data provides further evidence for the essential roles of primary cilia and hedgehog signaling in cranial base development and chondrocyte maturation, and point to a close interdependence between cilia and HS-PGs to delimit targets of hedgehog action in synchondroses.

scholarly journals The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Saishu Yoshida ◽  
Katsuhiko Aoki ◽  
Ken Fujiwara ◽  
Takashi Nakakura ◽  
Akira Kawamura ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
The Novel ◽  
Mammalian Development ◽  
Hh Signaling ◽  
Functional Analyses ◽  
First Time ◽  
Insight Into

Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

scholarly journals KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Petra Pejskova ◽  
Madeline Louise Reilly ◽  
Lucia Bino ◽  
Ondrej Bernatik ◽  
Linda Dolanska ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
Aurora A ◽  
Pathway Activation ◽  
Cilia Formation ◽  
Tightly Coupled ◽  
Hh Signaling

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

scholarly journals The Role of Glypicans in Cancer Progression and Therapy

2020 ◽  
Vol 68 (12) ◽  
pp. 841-862 ◽  
Author(s):  
Nan Li ◽  
Madeline R. Spetz ◽  
Mitchell Ho
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Growth Factors ◽  
Heparan Sulfate ◽  
Cancer Progression ◽  
Core Protein ◽  
Heparan Sulfate Proteoglycans ◽  
Glycosylphosphatidylinositol Anchor ◽  
Multiple Ligands

Glypicans are a family of heparan sulfate proteoglycans that are attached to the cell membrane via a glycosylphosphatidylinositol anchor. Glypicans interact with multiple ligands, including morphogens, growth factors, chemokines, ligands, receptors, and components of the extracellular matrix through their heparan sulfate chains and core protein. Therefore, glypicans can function as coreceptors to regulate cell proliferation, cell motility, and morphogenesis. In addition, some glypicans are abnormally expressed in cancers, possibly involved in tumorigenesis, and have the potential to be cancer-specific biomarkers. Here, we provide a brief review focusing on the expression of glypicans in various cancers and their potential to be targets for cancer therapy.

scholarly journals Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery

2008 ◽  
Vol 180 (5) ◽  
pp. 897-904 ◽  
Author(s):  
Enko N. Kiprilov ◽  
Aashir Awan ◽  
Romain Desprat ◽  
Michelle Velho ◽  
Christian A. Clement ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Embryonic Stem ◽  
Serum Starvation ◽  
Mechanistic Basis ◽  
Patched 1 ◽  
Hesc Lines

Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC differentiation, demonstrating the existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation. Using electron microscopy (EM), immunofluorescence, and confocal microscopies, we show that primary cilia are present in three undifferentiated hESC lines. EM reveals the characteristic 9 + 0 axoneme. The number and length of cilia increase after serum starvation. Important components of the hedgehog (Hh) pathway, including smoothened, patched 1 (Ptc1), and Gli1 and 2, are present in the cilia. Stimulation of the pathway results in the concerted movement of Ptc1 out of, and smoothened into, the primary cilium as well as up-regulation of GLI1 and PTC1. These findings show that hESCs contain primary cilia associated with working Hh machinery.

scholarly journals EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling

2017 ◽  
Vol 114 (49) ◽  
pp. E10532-E10539 ◽  
Author(s):  
Vincent J. Guen ◽  
Tony E. Chavarria ◽  
Cornelia Kröger ◽  
Xin Ye ◽  
Robert A. Weinberg ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Adult Stem Cells ◽  
Primary Cilia ◽  
Epithelial Mesenchymal Transition ◽  
Mammary Epithelium ◽  
Mammary Tissue ◽  
Small Subset ◽  
Tumor Initiating Cells ◽  
Mesenchymal Transition ◽  
Hh Signaling

Tissue regeneration relies on adult stem cells (SCs) that possess the ability to self-renew and produce differentiating progeny. In an analogous manner, the development of certain carcinomas depends on a small subset of tumor cells, called “tumor-initiating cells” (TICs), with SC-like properties. Mammary SCs (MaSCs) reside in the basal compartment of the mammary epithelium, and their neoplastic counterparts, mammary TICs (MaTICs), are thought to serve as the TICs for the claudin-low subtype of breast cancer. MaSCs and MaTICs both use epithelial–mesenchymal transition (EMT) programs to acquire SC properties, but the mechanism(s) connecting EMT programs to stemness remain unclear. Here we show that this depends on primary cilia, which are nonmotile, cell-surface structures that serve as platforms for receiving cues and enable activation of various signaling pathways. We show that MaSC and MaTIC EMT programs induce primary cilia formation and Hedgehog (Hh) signaling, which has previously been implicated in both MaSC and MaTIC function. Moreover, ablation of these primary cilia is sufficient to repress Hh signaling, the stemness of MaSCs, and the tumor-forming potential of MaTICs. Together, our findings establish primary ciliogenesis and consequent Hh signaling as a key mechanism by which MaSC and MaTIC EMT programs promote stemness and thereby support mammary tissue outgrowth and tumors of basal origin.

scholarly journals Thyroid Hormone Regulates Heparan Sulfate Proteoglycan Expression in the Growth Plate

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 295-305 ◽  
Author(s):  
J. H. D. Bassett ◽  
R. Swinhoe ◽  
O. Chassande ◽  
J. Samarut ◽  
G. R. Williams
Keyword(s):  
Thyroid Hormone ◽  
Heparan Sulfate ◽  
Growth Plate ◽  
Hedgehog Signaling ◽  
Hormone Receptors ◽  
Core Protein ◽  
Skeletal Development ◽  
Indian Hedgehog ◽  
Fgf Receptor ◽  
Modification Enzyme

Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRα/TRβ double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T3 regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T3. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone.

scholarly journals Hedgehog Signaling and Truncated GLI1 in Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2114 ◽  
Author(s):  
Daniel Doheny ◽  
Sara G. Manore ◽  
Grace L. Wong ◽  
Hui-Wen Lo
Keyword(s):  
Hedgehog Signaling ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Human Cancers ◽  
Cell Growth And Differentiation ◽  
Hh Signaling ◽  
Patched 1 ◽  
Truncated Variants

The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

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