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 Amalgam regulates the receptor tyrosine kinase pathway through Sprouty in glial cell development in the Drosophila larval brain

2020 ◽  
Vol 133 (19) ◽  
pp. jcs250837
Author(s):  
Majd M. Ariss ◽  
Alexander R. Terry ◽  
Abul B. M. M. K. Islam ◽  
Nissim Hay ◽  
Maxim V. Frolov
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Glial Cell ◽  
Receptor Tyrosine Kinase ◽  
Cell Development ◽  
Negative Regulator ◽  
Larval Brain ◽  
Adhesion Protein ◽  
Type Composition ◽  
Signaling Activation

ABSTRACTThe receptor tyrosine kinase (RTK) pathway plays an essential role in development and disease by controlling cell proliferation and differentiation. Here, we profile the Drosophila larval brain by single-cell RNA-sequencing and identify Amalgam (Ama), which encodes a cell adhesion protein of the immunoglobulin IgLON family, as regulating the RTK pathway activity during glial cell development. Depletion of Ama reduces cell proliferation, affects glial cell type composition and disrupts the blood–brain barrier (BBB), which leads to hemocyte infiltration and neuronal death. We show that Ama depletion lowers RTK activity by upregulating Sprouty (Sty), a negative regulator of the RTK pathway. Knockdown of Ama blocks oncogenic RTK signaling activation in the Drosophila glioma model and halts malignant transformation. Finally, knockdown of a human ortholog of Ama, LSAMP, results in upregulation of SPROUTY2 in glioblastoma cell lines, suggesting that the relationship between Ama and Sty is conserved.

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 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 Connexin 43 and Sonic Hedgehog Pathway Interplay in Glioblastoma Cell Proliferation and Migration

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 767
Author(s):  
Filippo Torrisi ◽  
Cristiana Alberghina ◽  
Debora Lo Furno ◽  
Agata Zappalà ◽  
Samuel Valable ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Cx43 Expression ◽  
Close Link ◽  
Shh Pathway ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Glioblastoma (GBM) represents the most common primary brain tumor within the adult population. Current therapeutic options are still limited by high rate of recurrences and signalling axes that promote GBM aggressiveness. The contribution of gap junctions (GJs) to tumor growth and progression has been proven by experimental evidence. Concomitantly, tumor microenvironment has received increasing interest as a critical process in dysregulation and homeostatic escape, finding a close link between molecular mechanisms involved in connexin 43 (CX43)-based intercellular communication and tumorigenesis. Moreover, evidence has come to suggest a crucial role of sonic hedgehog (SHH) signalling pathway in GBM proliferation, cell fate and differentiation. Herein, we used two human GBM cell lines, modulating SHH signalling and CX43-based intercellular communication in in vitro models using proliferation and migration assays. Our evidence suggests that modulation of the SHH effector smoothened (SMO), by using a known agonist (i.e., purmorphamine) and a known antagonist (i.e., cyclopamine), affects the CX43 expression levels and therefore the related functions. Moreover, SMO activation also increased cell proliferation and migration. Importantly, inhibition of CX43 channels was able to prevent SMO-induced effects. SHH pathway and CX43 interplay acts inducing tumorigenic program and supporting cell migration, likely representing druggable targets to develop new therapeutic strategies for GBM.

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

2010 ◽  
Vol 121 (2) ◽  
pp. 229-239 ◽  
Author(s):  
Hani Al-Halabi ◽  
Andre Nantel ◽  
Almos Klekner ◽  
Marie-Christine Guiot ◽  
Steffen Albrecht ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Pathway ◽  
Sonic Hedgehog Pathway ◽  
Adult Medulloblastoma ◽  
Pathway Activation

scholarly journals Sonic Hedgehog Pathway Activation Is Induced by Acute Brain Injury and Regulated by Injury-Related Inflammation

2009 ◽  
Vol 29 (33) ◽  
pp. 10299-10308 ◽  
Author(s):  
N. M. Amankulor ◽  
D. Hambardzumyan ◽  
S. M. Pyonteck ◽  
O. J. Becher ◽  
J. A. Joyce ◽  
...  
Keyword(s):  
Brain Injury ◽  
Sonic Hedgehog ◽  
Acute Brain Injury ◽  
Hedgehog Pathway ◽  
Sonic Hedgehog Pathway ◽  
Pathway Activation
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