Dispatching Sonic Hedgehog: Molecular Mechanisms Controlling Deployment

Hall, Eric T.; Cleverdon, Elizabeth R.; Ogden, Stacey K.

doi:10.1016/j.tcb.2019.02.005

Cited by 42 publications

(43 citation statements)

References 66 publications

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“…Our analysis identified a rare age-associated variant within DISP2, in which epigenetic mapping revealed to be located within an enhancer specific to primitive neural cells. DISP2 is an upstream effector of SHH signaling with roles in embryonic development and is highly expressed neural tissue (Hall et al, 2019). In the absence of Disp, hedgehog ligands fail to release from donor cells, resulting in impaired early neural and embryonic development (Burke et al, 1999;Ma et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Sin‐Chan

Gosalia

Gao

et al. 2020

Preprint

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Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males greater than 92 years, Females greater than 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

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Section: Discussionmentioning

confidence: 99%

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Sin‐Chan

Gosalia

Gao

et al. 2020

Preprint

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“…Because Scube2-regulated Hh release is known to also require Disp (Hall et al, 2019), we expected strongly impaired Shh shedding from cells made deficient in Disp function. To test this hypothesis, we generated Disp knockout cells (Disp -/-) by using CRISPR/Cas9.…”

Section: Scube2 Increases Shh Shedding From Disp-expressing Cellsmentioning

confidence: 99%

“…What makes these questions particularly interesting is that the Hh release protein Disp on Hh producing cells is structurally related to the Hh receptor Patched (Ptc) on Hh receiving cells (Hall, Cleverdon, & Ogden, 2019). Both proteins contain 12 transmembrane helices and 2 extracellular domains and belong to the resistance-nodulation-division (RND) family of transmembrane efflux pumps.…”

Section: Introductionmentioning

confidence: 99%

“…Normally, such pumps maintain cellular homeostasis and remove toxic compounds. In addition, both proteins contain a conserved domain known as the sterolsensing domain (SSD) that is involved in different aspects of homeostasis of free or esterified cellular cholesterol in other SSD proteins (Hall et al, 2019). These striking structural resemblances between Ptc and Disp and the conserved SSD constitute another unexplained feature of the Hh pathway because they imply that similar -possibly cholesterol relatedmechanisms control the opposite functions of Hh release from producing cells and Hh perception at receiving cells.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, Disp activity alone is insufficient to deploy the vertebrate Hh family member Sonic hedgehog (Shh) from the plasma membrane of cells that express it. A second required synergistic factor required for maximum Shh signaling has been identified as the secreted glycoprotein Scube2 (Signal sequence, cubulin (CUB) domain, epidermal growth factor (EGF)-like protein 2) (Hall et al, 2019). One way to explain this synergy is that Disp may be required to extract lipidated Shh from the plasma membrane and hand it over to Scube2.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Conserved cholesterol-related activities of Dispatched drive Sonic hedgehog shedding from the cell membrane

Ehring

Manikowski

Froese

et al. 2020

Preprint

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The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells, and how the resistance-nodulation-division transporter Dispatched (Disp) regulates this process. Here we show that Disp inactivation in Shh expressing cells specifically impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. Shh shedding from Disp-deficient cells was restored by pharmacological membrane cholesterol extraction and by overexpressed transgenic Disp or structurally related Patched (Ptc, a putative cholesterol transporter). These data suggest that Disp regulates physiological Shh function via controlled cell surface shedding and that molecular mechanisms shared by Disp and Ptc exercise such sheddase control.

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Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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Dispatching Sonic Hedgehog: Molecular Mechanisms Controlling Deployment

Cited by 42 publications

References 66 publications

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Conserved cholesterol-related activities of Dispatched drive Sonic hedgehog shedding from the cell membrane

Small molecule inhibitors targeting the cancers

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