Article
Biochemistry & Molecular Biology
Xuguang Jiang, Tadayuki Ogawa, Kento Yonezawa, Nobutaka Shimizu, Sotaro Ichinose, Takayuki Uchihashi, Wataru Nagaike, Toshio Moriya, Naruhiko Adachi, Masato Kawasaki, Naoshi Dohmae, Toshiya Senda, Nobutaka Hirokawa
Summary: This study reveals the molecular mechanism of specific and dynamic cargo-binding of kinesin complexes. The two-step cargo recognition and stabilization mechanism of kinesins provides novel insights into intracellular trafficking machinery.
Review
Cell Biology
Mengmeng Zhou, Jin Jiang
Summary: The Hedgehog (Hh) family of secreted proteins play important roles in embryonic development and adult tissue homeostasis. Dysregulation of Hh signaling is associated with various human diseases. The activation and repression of the transcription factor Cubitus interruptus (Ci)/Gli in the Hh signaling pathway is regulated by phosphorylation, including phosphorylation by protein kinase A (PKA), glycogen synthase kinase 3 (GSK3), and casein kinase 1 (CK1), as well as by Fused (Fu)/Unc-51 like kinase (Ulk) family kinases such as Fu/Ulk3/Stk36. Phosphorylation of Ci/Gli influences its interaction with the Hh pathway repressor Sufu and affects Hh signal transduction.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
B. Baran, K. Kosieradzka, W. Skarzynska, P. Niewiadomski
Summary: In this study, three novel kinases, MRCK alpha, MRCK beta, and MAP4K5, were identified to interact with Gli proteins and phosphorylate Gli2 on multiple sites. It was demonstrated that MRCK alpha/beta kinases regulate Gli proteins, which in turn affects the transcriptional output of the Hedgehog pathway. The research provides important insights into the phosphorylation-based activation mechanisms of Gli proteins.
CELLULAR SIGNALLING
(2023)
Article
Medicine, Research & Experimental
Chao Tang, Ximei Wu, Qianlei Ren, Minli Yao, Shouying Xu, Ziyi Yan
Summary: This study uncovers a novel mechanism controlling Hh signaling through the activation of Rac1 and subsequent translocation of Gli. Rac1 activation affects KIF3A phosphorylation and IFT88 stability, thereby disrupting SuFu-Gli complex formation and releasing Gli for nuclear translocation.
Review
Immunology
Yazhen Su, Hao Xing, Jie Kang, Linkun Bai, Liyun Zhang
Summary: The Hedgehog (Hh) signaling pathway plays a crucial role in rheumatic diseases and has the potential to be a therapeutic target.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Pharmacology & Pharmacy
Xiaohua Liu, Yu Zhang, Yalei Li, Juan Wang, Huaqian Ding, Wenjing Huang, Chunyong Ding, Hongchun Liu, Wenfu Tan, Ao Zhang
Summary: Medulloblastoma is a childhood malignant brain tumor with heterogeneous characteristics and lacks effective molecular targeted therapy. Compounds 25 and 35 show high potency in inhibiting hedgehog signaling and interacting with the transcriptional factor GLI, with potential to combat resistant and wild type smoothened receptor.
ACTA PHARMACEUTICA SINICA B
(2021)
Review
Cell Biology
Chamey Suchors, James Kim
Summary: The Hedgehog signaling pathway is crucial for development and tissue regeneration, and its dysregulation has been linked to cancer. Our understanding of this pathway in tumorigenesis has significantly advanced over the past few decades. The pathway can have both tumor-suppressive and oncogenic functions, and noncanonical activation of GLI transcription factors has been observed in certain types of tumors.
Article
Biochemistry & Molecular Biology
Ignazia Tusa, Sinforosa Gagliardi, Alessandro Tubita, Silvia Pandolfi, Alessio Menconi, Matteo Lulli, Persio Dello Sbarba, Barbara Stecca, Elisabetta Rovida
Summary: The study identified a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, showing that activation of the Hedgehog-GLI pathway increased ERK5 expression and that inhibitors targeting both pathways were more effective in reducing melanoma cell viability and colony formation compared to single treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biology
Fan Yang, Daniel T. Wynn, Chen Shen, Nagi G. Ayad, David J. Robbins
Summary: The Hedgehog signaling pathway is crucial for embryonic development and tissue homeostasis, but its abnormal activation is implicated in various cancers. GLI transcription factors act as the ultimate effectors of this pathway and their activity is regulated by multiple mechanisms. Recent studies have found that novel protein complexes can also regulate the transcriptional activity of GLI proteins, providing innovative druggable targets for GLI-dependent cancers.
Article
Multidisciplinary Sciences
Rachel K. Lex, Weiqiang Zhou, Zhicheng Ji, Kristin N. Falkenstein, Kaleigh E. Schuler, Kathryn E. Windsor, Joseph D. Kim, Hongkai Ji, Steven A. Vokes
Summary: The study challenges the current understanding that GLI3 repression is established before Hedgehog (HH) signaling and demonstrates that GLI3 is inert in the limb bud before HH onset. The loss of Gli3 does not increase target gene expression or accessibility, contrasting with post-HH signaling. GLI repression is established independently of HH signaling, but after its onset.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Marzena Swiderska-Syn, Julia Mir-Pedrol, Alexander Oles, Olga Schleuger, April D. Salvador, Sean M. Greiner, Cara Seward, Fan Yang, Benjamin R. Babcock, Chen Shen, Daniel T. Wynn, Avencia Sanchez-Mejias, Timothy R. Gershon, Vanesa Martin, Heather J. McCrea, Kathryn G. Lindsey, Carsten Krieg, Jezabel Rodriguez-Blanco
Summary: Single-cell transcriptomic analysis of medulloblastoma revealed that vismodegib treatment increased Sox2-expressing astrocyte-like cells. These Sox2(+) cells relied on Sonic Hedgehog (SHH) signaling, with MYC-dependent activation downstream of Smo. GLI inhibitors depleted resistant Sox2(+) cells, reduced their engraftment ability, and increased symptom-free survival.
Article
Developmental Biology
Nicole Roberto, Isabelle Becam, Anne Plessis, Robert A. Holmgren
Summary: Morphogen gradients require robustness and can be tailored for specific tissues through negative regulators and feedback loops. In the Drosophila wing imaginal disc, genes like Engrailed and Roadkill modulate Hh signaling and affect the formation of the Hh gradient.
Article
Oncology
Wenjing Huang, Han Liu, Wenfu Tan, Juan Wang
Summary: ABT-737 is identified as a selective Hh inhibitor that suppresses Hh signals far downstream of Smo and inhibits both wild-type and drug-resistant mutant Smo. It also delays the growth of drug-refractory Hh-dependent MB xenografts.
Article
Chemistry, Medicinal
Manuel Mendoza, UyenPhuong Tran, Grace C. Zhang, Jeffrey Leister, Kyle To, Theodore Malepeai-Tofaeono, Alison E. Ondrus, Kelvin L. Billingsley
Summary: The Gli transcription factors within the Hedgehog signaling pathway have crucial roles in human development, but their reactivation in adult tissue is tumorigenic. This study identifies a set of indolactam dipeptides that can inhibit the activity of Gli proteins, thereby blocking the growth of basal cell carcinoma cells. These findings provide new avenues for developing treatments for Gli-driven cancers.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Oncology
Ashley N. Sigafoos, Brooke D. Paradise, Martin E. Fernandez-Zapico
Summary: The Hedgehog/GLI pathway is crucial during development and often dysregulated in diseases like cancer. Activation in cancer is typically through a non-canonical, ligand-independent mechanism. This pathway involves a series of components that work together to repress or activate signaling cascades.
Article
Biology
David S. Lorberbaum, Andrea I. Ramos, Kevin A. Peterson, Brandon S. Carpenter, David S. Parker, Sandip De, Lauren E. Hillers, Victoria M. Blake, Yuichi Nishi, Matthew R. McFarlane, Ason C. Y. Chiang, Judith A. Kassis, Benjamin L. Allen, Andrew P. McMahon, Scott Barolo
Article
Biology
Teresa Wei-sy Lee, Heidi Shira David, Amanda Kathryn Engstrom, Brandon Scott Carpenter, David John Katz
Article
Developmental Biology
Brandon S. Carpenter, Teresa W. Lee, Caroline F. Plott, Juan D. Rodriguez, Jovan S. Brockett, Dexter A. Myrick, David J. Katz
Summary: The study demonstrates that in Caenorhabditis elegans, MES-4 protects key germline genes by preventing reprogramming, thus avoiding developmental delays.