Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous Smo (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.molcel.2017.02.015 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Hypothyroidism Alters Uterine Kisspeptin System and Activity Modulators in Cyclic Rats.
Int J Mol Sci
January 2025
Electron Microscopy Center, Department of Biological Sciences, State University of Santa Cruz, Ilheus 45662-900, Brazil.
Hypothyroidism causes ovarian dysfunction and infertility in women and animals and impairs the hypothalamic expression of kisspeptin (Kp). However, kisspeptin is also expressed in the genital system, and the lack of the Kp receptor (Kiss1r) in the uterus is linked to reduced implantation rates. This study investigated the impact of hypothyroidism on the uterine expression of Kp and Kiss1r in female rats throughout the estrous cycle and the associated changes in uterine activity modulators.
View Article and Find Full Text PDFClinical and molecular characteristics and long-term outcomes of pediatric intracranial meningiomas: a comprehensive analysis from a single neurosurgical center.
Acta Neuropathol Commun
January 2025
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Background: Meningioma represents the most common intracranial tumor in adults. However, it is rare in pediatric patients. We aimed to demonstrate the clinicopathological characteristics and long-term outcome of pediatric meningiomas (PMs).
View Article and Find Full Text PDFIncidence of severe maternal outcomes following armed conflict in East Gojjam zone, Amhara region, Ethiopia: using the sub-Saharan Africa maternal near-miss criteria.
Front Public Health
January 2025
Department of Midwifery, Asrat Woldeyes Health Science Campus, Debre Berhan University, Debre Berhan, Ethiopia.
Background: Severe maternal outcome (SMO) encompasses women who survive life-threatening conditions either by chance or due to treatment quality, or who die. This concept assumes that severe maternal morbidity predicts mortality risk, enabling the analysis of risk factors for life-threatening outcomes and improving our understanding on the causes of maternal death. This study aims to determine the incidence of SMO and its leading causes in East Gojjam during a period of regional conflict.
View Article and Find Full Text PDFGlypican-3 is a key tuner of the Hedgehog pathway in COPD.
Heliyon
January 2025
Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France.
Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD).
View Article and Find Full Text PDFThe role of 1-Deoxysphingolipids and Polyamines in the pathogenesis of placental syndrome.
BMC Pregnancy Childbirth
January 2025
Department of Basic Pharmaceutical Sciences, Division of Biochemistry, Recep Tayyip Erdogan University, Rize, Turkey.
Background: Placental syndrome, mainly composed of preeclampsia and fetal growth restriction, has an impact on the health of mother and baby dyads. While impaired placentation is central to their pathophysiology, the underlying molecular mechanisms remain incompletely understood. This study investigates the association between placental syndrome and metabolic alterations in 1-deoxysphingolipids (1-deoxySLs) and polyamines, along with their regulatory enzymes.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!