Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma

Atwood, Scott X.; Sarin, Kavita Y.; Li, Jiang R.; Yao, Chia-Yu; Urman, Nicole M.; Chang, Anne Lynn S.; Tang, Jean Y.; Oro, Anthony E.

doi:10.1038/jid.2015.115

Cited by 20 publications

(24 citation statements)

References 9 publications

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“…We previously performed whole exome and targeted re-sequencing of 58 sporadic and Gorlin’s Syndrome BCC samples and found expected mutations in PTCH1 and SMO in accordance with our previous publications [6,7]. Interestingly, we also identified 9 SUFU variants, many of which had not been previously described.…”

Section: Resultssupporting

confidence: 89%

Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

et al. 2016

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The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

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Section: Resultssupporting

confidence: 89%

Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

et al. 2016

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“…Activating mutations of Smo (e.g., V321M, L412F, F460L, W535L and R562Q) have strong effects on its activity and can drive the formation of basal cell cancer and medulloblastoma(36–38). Several Smo inhibitors, such as cyclopamine, IPI-926, GDC-0449 and LDE-225, are currently in clinical trials for various cancer treatments(39–42).…”

Section: Discussionmentioning

confidence: 99%

Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway

Shao

Chen

et al. 2017

Cancer Research

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Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking and localization which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration and invasion in vitro and in vivo. In clinical specimens of gastric cancer, Arl13b expression correlated strongly with tumor size and depth of invasion; patients with high levels of Arl13b had a poor prognosis. Our results show how Arl13b participates in Hh pathway activation in gastric cancer.

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“…Documented mutations fall into one of three categories depending upon their impact on signaling. The first are passenger mutations, which can occur in a number of tumor types, but have minimal impact on signaling or ligand binding [94, 95]. Conversely, activating mutations have profound effects on Smo activity, and can serve as driving mutations in basal cell carcinoma and medulloblastoma [94].…”

Section: Figurementioning

confidence: 99%

“…The first are passenger mutations, which can occur in a number of tumor types, but have minimal impact on signaling or ligand binding [94, 95]. Conversely, activating mutations have profound effects on Smo activity, and can serve as driving mutations in basal cell carcinoma and medulloblastoma [94]. These mutations affect the TM domains or carboxyl-tail, and are thought to induce conformation shifts that drive ligand-independent signaling.…”

Section: Figurementioning

confidence: 99%

“…This lesion is localized to the seventh transmembrane helix and impacts a region commonly considered to be a trigger point for activation of Class A GPCRs [17, 95]. V231M, L412 and F460L affect TM domains 3, 5 and 6, which are essential pivot regions for activation of stereotypical GPCRs, and likely activate Smo by mimicking its ligand-induced active conformation [94]. The carboxyl-terminal tail mutation R562Q is adjacent to the first conserved GRK2 phosphorylation cluster, and could potentially trigger ligand-independent signaling through altering conformation of this important regulatory domain [43].…”

Section: Figurementioning

confidence: 99%

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Smoothened Regulation: A Tale of Two Signals

Arensdorf

Marada

Ogden

2016

Trends in Pharmacological Sciences

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The G protein-coupled receptor Smoothened (Smo) is the signal transducer of the developmentally- and therapeutically-relevant Hedgehog pathway. Although recent structural analyses have advanced our understanding of Smo biology, a number of questions remain. Chief among them are the identity of its natural ligand, the regulatory processes controlling its activation, and the mechanisms by which it signals to downstream effectors. This review will discuss recent discoveries from multiple model systems that have set the stage for solving these mysteries. We focus on the roles of distinct Smo functional domains, post-translational modifications and trafficking, and conclude by discussing their contributions to signal output.

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Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma

Cited by 20 publications

References 9 publications

Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway

Smoothened Regulation: A Tale of Two Signals

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