scholarly journals Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Shen Yue ◽  
Liu-Ya Tang ◽  
Ying Tang ◽  
Yi Tang ◽  
Qiu-Hong Shen ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Feedback Loop ◽  
Hect Domain ◽  
E3 Ligases ◽  
Caveolin 1 ◽  
Shh Pathway ◽  
Sorting Signals ◽  
Pathway Activation ◽  
Endocytic Sorting ◽  
Hedgehog Signal

Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two ‘PPXY’ motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal.

scholarly journals Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation

2018 ◽  
Vol 116 (3) ◽  
pp. 874-879 ◽  
Author(s):  
Boyan Zhang ◽  
Tenghan Zhuang ◽  
Qiaoyu Lin ◽  
Biying Yang ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Initial Step ◽  
Negative Regulator ◽  
Individual Development ◽  
Sonic Hedgehog Pathway ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Mother Centriole ◽  
Signaling Activation

The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.

scholarly journals Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest

1999 ◽  
Vol 147 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Hongran Fan ◽  
Paul A. Khavari
Keyword(s):  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Cycle Arrest ◽  
Sonic Hedgehog ◽  
Growth Arrest ◽  
Epidermal Hyperplasia ◽  
Shh Pathway ◽  
Cycle Arrest ◽  
Pathway Activation

Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21CIP1/WAF1-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.

scholarly journals Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

2017 ◽  
Vol 28 (3) ◽  
pp. 387-395 ◽  
Author(s):  
Pamela J. Yao ◽  
Uri Manor ◽  
Ronald S. Petralia ◽  
Rebecca D. Brose ◽  
Ryan T. Y. Wu ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hippocampal Neurons ◽  
Mitochondrial Fission ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Peptide Hydrogen ◽  
And Function

Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons.

Effect of Sonic hedgehog activation on CXCR7 expression and CXCR4 signaling in medulloblastoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13537-e13537
Author(s):  
Stacey Anne Ward ◽  
Rajarshi Sengupta ◽  
Joshua Rubin
Keyword(s):  
Tumor Cells ◽  
Sonic Hedgehog ◽  
Granule Cells ◽  
Single Cells ◽  
Primary Cultures ◽  
Normal Cells ◽  
Cxcr4 Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Surface Localization

e13537 Background: Stratification of pediatric medullolastoma into molecular subtypes elevates hopes that subtype-specific therapy can be more efficacious and less toxic. To realize this goal, the molecular targets that distinguish each subtype must be defined. We found that Sonic hedgehog (Shh)-subtype medulloblastoma can be further divided by CXCR4 expression and that CXCR4 inhibition has potent anti-tumor effects. Here we present data that Shh regulates CXCR4 activity through CXCR7, whose differential expression between normal granule cells and medulloblastoma cells makes its function an ideal therapeutic target. Methods: Single-cell suspensions were plated with or without Shh or cyclopamine followed by treatment with CXCL12. SmoA1 brain tumors were dissociated into single cells and transplanted into nude mice and treated with vehicle, AMD3100, GDC-0449, or both. Tumors were measured and harvested at the conclusion of treatment. Results: Using primary cultures of Shh-driven medulloblastoma we found that Shh activation enhances CXCR4 surface localization and promotes CXCL12-induced signaling, similar to effects of Shh on normal granule cells. We evaluated expression of CXCR4 internalization regulators and found that Shh activation altered the levels of GRKs, arrestins and CXCR7. Among these, CXCR7 expression exhibited the greatest differential response to Shh pathway activation between normal cells and medulloblastoma: CXCR7 expression was highly expressed in normal cells despite Shh effects, but almost completely absent in tumor cells. Conclusions: We conclude that activation of the Shh pathway in medulloblastomas promotes CXCR4 surface localization through inhibition of internalization mediators. This cross-talk is also evident in developing GPCs but with one notable difference: CXCR7 expression (high in normal cells, absent in tumor cells). This distinction suggests that CXCR7 antagonists, which are moving towards clinical trials, may be detrimental to normal cerebellar development and inactive against medulloblastoma. We propose that restoring CXCR7 activity would have negligible effects on granule cells and potently block CXCR4 function in medulloblastoma.

scholarly journals Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 323 ◽  
Author(s):  
Daniele Tibullo ◽  
Anna Longo ◽  
Nunzio Vicario ◽  
Alessandra Romano ◽  
Alessandro Barbato ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Bone Remodeling ◽  
Sonic Hedgehog ◽  
Bone Disease ◽  
Human Mscs ◽  
Bone Homeostasis ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Osteolytic Bone Disease

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients.

scholarly journals Dysgerminoma with a Somatic Exon 17 KIT Mutation and SHH Pathway Activation in a Girl with Turner Syndrome

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1067
Author(s):  
Ada Gawrychowska ◽  
Ewa Iżycka-Świeszewska ◽  
Beata S. Lipska-Ziętkiewicz ◽  
Dominika Kuleszo ◽  
Joanna Bautembach-Minkowska ◽  
...  
Keyword(s):  
Turner Syndrome ◽  
Sonic Hedgehog ◽  
Neoplastic Tissue ◽  
Kit Mutation ◽  
Shh Pathway ◽  
Oncogenic Pathway ◽  
First Case ◽  
Pathway Activation ◽  
Kit Gene ◽  
Ovarian Dysgerminoma

This article reports a case of a 7-year-old girl with Turner syndrome, treated with growth hormone (GH), who developed ovarian dysgerminoma. The patient karyotype was mosaic for chromosome Xq deletion: 46,X,del(X)(q22)/45,X. No Y chromosome sequences were present. Molecular studies revealed the presence of a driving mutation in exon 17 of the KIT gene in the neoplastic tissue, as well as Sonic-hedgehog (SHH) pathway activation at the protein level. The patient responded well to chemotherapy and remained in complete remission. This is the first case of dysgerminoma in a Turner syndrome patient with such oncogenic pathway.

scholarly journals Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis

2021 ◽  
Author(s):  
Xiaodong Li ◽  
Patrick J Gordon ◽  
John A Gaynes ◽  
Alexandra W Fuller ◽  
Randy Ringuette ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Downstream Targets ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Retinal Neurogenesis

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

scholarly journals Pirh2, an E3 ligase, regulates the AIP4–p73 regulatory pathway by modulating AIP4 expression and ubiquitination

2021 ◽  
Author(s):  
Rami Abou Zeinab ◽  
H Helena Wu ◽  
Yasser Abuetabh ◽  
Sarah Leng ◽  
Consolato Sergi ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Ectopic Expression ◽  
E3 Ligase ◽  
Regulatory Pathway ◽  
Hect Domain ◽  
E3 Ligases ◽  
Multiple Substrates ◽  
Protein Levels ◽  
Cycle Arrest ◽  
Negative Regulatory Pathway

Abstract Pirh2 is an E3 ligase belonging to the RING-H2 family and shown to bind, ubiquitinate and downregulate p73 tumor suppressor function without altering p73 protein levels. AIP4, an E3 ligase belonging to the HECT domain family, has been reported to be a negative regulatory protein that promotes p73 ubiquitination and degradation. Herein, we found that Pirh2 is a key regulator of AIP4 that inhibits p73 function. Pirh2 physically interacts with AIP4 and significantly downregulates AIP4 expression. This downregulation is shown to involve the ubiquitination of AIP4 by Pirh2. Importantly, we demonstrated that the ectopic expression of Pirh2 inhibits the AIP4–p73 negative regulatory pathway, which was restored when depleting endogenous Pirh2 utilizing Pirh2-siRNAs. We further observed that Pirh2 decreases AIP4-mediated p73 ubiquitination. At the translational level and specifically regarding p73 cell cycle arrest function, Pirh2 still ensures the arrest of p73-mediated G1 despite AIP4 expression. Our study reveals a novel link between two E3 ligases previously thought to be unrelated in regulating the same effector substrate, p73. These findings open a gateway to explain how E3 ligases differentiate between regulating multiple substrates that may belong to the same family of proteins, as it is the case for the p53 and p73 proteins.

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