Review
Biochemistry & Molecular Biology
Jian Yi Chai, Vaisnevee Sugumar, Mohammed Abdullah Alshawsh, Won Fen Wong, Aditya Arya, Pei Pei Chong, Chung Yeng Looi
Summary: The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved in mammals and plays crucial roles in cancer initiation and progression. GLI transcription factors are regulated by both SMO-dependent and SMO-independent mechanisms, with dysregulation leading to tumorigenesis in various cancers. Understanding the complex interplay between GLI and signaling elements could inspire new therapeutic breakthroughs for Hh-GLI-dependent cancers.
Review
Cell Biology
Jianhang Jia, Jin Jiang
Summary: This review focuses on the essential role of Smoothened (Smo) protein in Hedgehog (Hh) signal transduction, as well as the regulatory mechanisms of Smo endocytosis and degradation in both insects and vertebrates. It discusses how Hh inhibits Smo ubiquitination and promotes Smo surface/ciliary accumulation through ubiquitin-specific protease 8 (USP8) in Drosophila, and also highlights the induction of sumoylation by Hh in regulating Smo trafficking and abundance in both Drosophila and mammalian cells.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Cell Biology
Jie Zhang, Zulong Liu, Jianhang Jia
Summary: SMO, a seven-transmembrane protein critical for hedgehog signal transduction, is regulated by multiple post-translational modifications and small molecules to maintain its activity balance and impact developmental defects and cancer initiation.
Article
Biochemistry & Molecular Biology
Junwan Fan, Haowen Li, Lun Kuang, Zichen Zhao, Wenyan He, Chen Liu, Yongjun Wang, Steven Y. Cheng, Wei Chen
Summary: A new Smoothened inhibitor, 0025A, has been discovered in this study, which effectively targets the Hedgehog signaling pathway and inhibits cancer cell activity. Additionally, it can suppress hair growth in mice.
CELL AND BIOSCIENCE
(2021)
Article
Neurosciences
Alice Del Giovane, Mariagiovanna Russo, Linda Tirou, Helene Faure, Martial Ruat, Sonia Balestri, Carola Sposato, Francesco Basoli, Alberto Rainer, Abdelmoumen Kassoussi, Elisabeth Traiffort, Antonella Ragnini-Wilson
Summary: This study shows that non-canonical signaling pathways can promote the maturation and regeneration of myelin cells, suggesting a potential role in the treatment of demyelinating diseases.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Junwan Fan, Zichen Zhao, Ru Liu, Haowen Li, Wenyan He, Jianping Wu, Yongjun Wang, Wei Chen
Summary: Our study found that the new Smoothened inhibitor TT22 can effectively block the translocation of β-arrestin2-GFP to Smoothened in neurons, reduce the accumulation of Smoothened on primary cilia, and inhibit the expression of downstream Gli transcription factor. In addition, TT22 also inhibits abnormal seizure-like activity in neurons.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Wanchen Wang, Ryo Shiraishi, Daisuke Kawauchi
Summary: The sonic hedgehog (SHH) pathway plays a crucial role in regulating the development of the central nervous system in vertebrates, and aberrant regulation can lead to neurodevelopmental diseases and brain tumors. Research on the mechanisms of SHH in the cerebellum has shed light on structural abnormalities and medulloblastoma, with current clinical trials exploring novel therapeutic approaches.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Developmental Biology
Wenguang Yin, Andreas Liontos, Janine Koepke, Maroua Ghoul, Luciana Mazzocchi, Xinyuan Liu, Chunyan Lu, Haoyu Wu, Athanasios Fysikopoulos, Alexandros Sountoulidis, Werner Seeger, Clemens Ruppert, Andreas Gunther, Didier Y. R. Stainier, Christos Samakovlis
Summary: The tracheal epithelium is a crucial element in pulmonary diseases, and its understanding of cell proliferation and differentiation is limited. The Hedgehog (HH) signaling pathway plays a role in communication between epithelial and mesenchymal cells in the lung, affecting stromal cell proliferation, differentiation, and epithelial signaling. This study discovered an autocrine HH signaling function in airway epithelial cells, with its inhibition leading to defects in cell proliferation and differentiation. Additionally, HH function is mediated by transcriptional activation, as inhibition of HH signaling downregulates cell type-specific transcription factor genes in both mouse trachea and human airway epithelial cells. These findings provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development.
Article
Cell Biology
Bo Lv, Xiao-Ou Zhang, Gregory J. Pazour
Summary: During Hedgehog signaling, Arih2 beta regulates the ER-associated degradation (ERAD) of Smo, preventing excess and potentially misfolded Smo from reaching the cilium and interfering with pathway regulation.
JOURNAL OF CELL SCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Kristian Kaber Pedersen, Maria Helena Hoyer-Hansen, Thomas Litman, Merete Haedersdal, Uffe Hogh Olesen
Summary: Systemic treatment with hedgehog inhibitors (HHis) is available for basal cell carcinomas, but limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on skin uptake, biological response, and time in tumor tissue. Current status of topical HHi delivery for BCCs is incomplete and there are barriers in terms of uptake, biodistribution, and biological response.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Ophthalmology
Jing-Yu Qu, Yu-Ting Xiao, Ying-Ying Zhang, Hua-Tao Xie, Ming-Chang Zhang
Summary: The Hedgehog signaling pathway plays an important role in regulating proliferation and differentiation of RMGECs, potentially offering a therapeutic approach for treating meibomian gland dysfunction (MGD).
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Article
Biology
Marina Goncalves Antunes, Matthieu Sanial, Vincent Contremoulins, Sandra Carvalho, Anne Plessis, Isabelle Becam
Summary: This study reveals how the hedgehog (HH) morphogen regulates the subcellular localization and activity of the oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO), thereby affecting the morphogenesis of epithelial structures. The authors provide evidence that HH promotes the recycling of internalized SMO, leading to its stabilization. This effect relies on the action of protein kinase A, casein kinase I, and Fused (FU) kinase. Additionally, at high HH levels, FU leads to the local enrichment of SMO in the basal domain of the cell membrane.
Article
Chemistry, Medicinal
Rakesh Pahwa, Jatin Chhabra, Raj Kumar, Rakesh Narang
Summary: This paper discusses key approaches to address resistance associated with melphalan, as well as chemical and formulation developments to enhance its characteristics and targeted profile. The rationale of the article also summarizes recent analytical methods, structure-activity relationship, pharmacokinetics, interactions, potential adverse effects, and medicinal updates of melphalan, including synthetic developments, derivatives, conjugates, and prodrugs, along with encouraging insights and research findings.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Omer Bayazeid, Taufiq Rahman
Summary: The study analyzed the molecular targets of 41 US FDA-approved kinase inhibitors, focusing on 18 tyrosine kinase inhibitors. By evaluating their selectivity profiles and interactions with multiple targets at clinically relevant doses, the research aimed to explore the correlation between target engagement profiles and reported side effects. The findings provide insights into the off-target effects of kinase inhibitors and their impact on toxicity, contributing to a better understanding of the structural-activity relationship of KIs.
Review
Oncology
Jian Yi Chai, Vaisnevee Sugumar, Ahmed F. Alshanon, Won Fen Wong, Shin Yee Fung, Chung Yeng Looi
Summary: The Hedgehog (Hh) signaling pathway plays a crucial role in cancer treatment, particularly in chemotherapy resistance. Understanding the mechanisms regulated by Hh signaling is essential for developing more effective treatment strategies in cancer therapy.
