A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development

Kong, Jennifer H.; Young, Cullen; Pusapati, Ganesh V.; Patel, C. A.; Ho, Sebastian; Krishnan, Arunkumar; Lin, Jeen‐Shang; Devine, William; Bellaing, Anne Moreau de; Athni, Tejas S.; Aravind, L.; Gunn, Teresa M.; Lo, Cecilia; Rohatgi, Rajat

doi:10.1016/j.devcel.2020.08.012

Cited by 24 publications

(36 citation statements)

References 86 publications

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“…As opposite to GLI3, the transmembrane protein MEGF8, which interacts with mahogunin ring finger-1 (MGRN1) for the ubiquitination and degradation of Smo, is not correlated with pancreatic cancer [ 117 ]. Likewise, limited evidence is reported for TTN , although it is now recognized as a tumor associated gene in several cancers including pancreatic cancer [ 118 ].…”

Section: Genetic and Molecular Features Of Pdac Variantsmentioning

confidence: 99%

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Bazzichetto

Luchini

Cognetti

et al. 2020

IJMS

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To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

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Section: Genetic and Molecular Features Of Pdac Variantsmentioning

confidence: 99%

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Bazzichetto

Luchini

Cognetti

et al. 2020

IJMS

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“…The cellular phenotypes (elevated ciliary SMO and sensitivity to SHH) and developmental defects (polydactyly, heterotaxy and CHDs) seen in Mosmo -/- embryos were reminiscent of those caused by the loss of either Megf8 or Mgrn1 and Rnf157 , components of a membrane-tethered E3 ubiquitin ligase complex that ubiquitinates SMO and accelerates its endocytosis and degradation (Kong et al, 2020) ( Figures 3A and S4C, Table S2 ). To determine if MEGF8 and MOSMO are part of the same pathway, we compared Hh signaling activity and SMO abundance in cells lacking each gene individually ( Mosmo -/- and Megf8 -/- single knockouts) to cells lacking both ( Mosmo -/- ; Megf8 -/- double knockouts).…”

Section: Resultsmentioning

confidence: 99%

“…A detailed list of phenotypes observed in each embryo can be found in Table S2. The Megf8 -/- phenotyping data is from our previous study (Kong et al, 2020). (B) Abundance of SMO and MEGF8 protein in whole cell lysates (top, 6.25% input) and on the cell-surface (bottom, cell surface biotinylation and streptavidin immunoprecipitation (IP), 50% elution) in NIH/3T3 cells of the indicated genotypes.…”

Section: Resultsmentioning

confidence: 99%

“…The cytoplasmic protein p38 serves as a loading control. (C-D) SMO ubiquitination was assessed after transient co-expression of the indicated proteins in HEK293T cells, as described in our previous study (Kong et al, 2020). Cells were lysed under denaturing conditions, SMO was purified by IP, and the amount of HA-tagged Ubiquitin (HA-UB) covalently conjugated to SMO was assessed using immunoblotting with an anti-HA antibody.…”

Section: Resultsmentioning

confidence: 99%

“…The phenotypic similarities between Mosmo -/- , Megf8 -/- , and Mgrn1 -/- ; Rnf157 -/- cells and mouse embryos supports the model that the MMM proteins function in the same pathway. We previously found that MGRN1 interacts with MEGF8, forming a membrane-tethered ubiquitination complex that targets SMO for degradation (Kong et al, 2020). Here, we report that MOSMO interacts with MEGF8 to facilitate its accumulation at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

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Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Kong

Young

Pusapati

et al. 2021

Preprint

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Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

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Molecular Pathways and Animal Models of Defects in Situs

Gabriel,

2024

Advances in Experimental Medicine and Biology

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A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development

Cited by 24 publications

References 86 publications

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Molecular Pathways and Animal Models of Defects in Situs

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