Smoothened Regulation: A Tale of Two Signals

Arensdorf, Angela M.; Marada, Suresh; Ogden, Stacey K.

doi:10.1016/j.tips.2015.09.001

Cited by 76 publications

(82 citation statements)

References 99 publications

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“…The relay of Hh signaling downstream of activated Smo is not yet completely understood. However, Smo activates both G-protein dependent and independent signals to regulate Gli transcription factors, calcium flux, and metabolic pathways (Arensdorf et al, 2016). Here, we will focus on signals that impinge on Gli transcription factors.…”

Section: Hh Signal Transductionmentioning

confidence: 99%

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

2016

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Summary The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly-regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights on regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies.

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Section: Hh Signal Transductionmentioning

confidence: 99%

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

2016

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“…Signaling via this pathway regulates the expression of several target genes (Figure 1). In mammals, the canonical hedgehog pathway requires the presence of the primary cilium (PC) (Arensdorf, Marada, and Ogden, 2016). Primary cilia (PC) are small immotile cilia comprised of polymerized tubulin.…”

Section: The Hedgehog Signaling Pathwaymentioning

confidence: 99%

“…In the absence of Hh, Ptch is on the PC and blocks Smo from entering the PC (Corbit et al, 2005)) and hence, Smo localizes in intracytoplasmic vesicles. When Hh binds to and inactivates Ptc (Rohatgi, Milenkovic, and Scott, 2007), Smo can move onto the PC (Arensdorf, Marada, and Ogden, 2016). The movement of Smo onto the PC is mediated by the kinesin motor protein Kif3A via an interaction that is dependent on beta-arrestins (Kovacs et al, 2008).…”

Section: The Hedgehog Signaling Pathwaymentioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

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Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

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“…Downstream effectors of Hh signal transduction, notably the transcription factors GLI2 and GLI3, are normally tethered by SUFU (suppressor of fused homolog) at the base of the primary cilium, where they are proteolytically processed to repressor forms (GLI2-R and GLI3-R, respectively). SMO activation leads to KIF7-dependent translocation toward the tip of the primary cilium and to transport of full-length activated GLI proteins (GLI2-A and GLI3-A) into the nucleus, enabling transcriptional activation (reviewed by Briscoe and Therond, 25 McCabe and Leahy, 26 and Arensdorf et al 27 ). Activation of the PI3K-AKT-mTOR and/or PKA pathways can independently lead to GLI activation, indicating the potential for significant cross-talk with the Hh pathway.…”

mentioning

confidence: 99%

A Recurrent Mosaic Mutation in SMO , Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

Twigg

Hufnagel

Miller

et al. 2016

The American Journal of Human Genetics

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Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.

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Smoothened Regulation: A Tale of Two Signals

Cited by 76 publications

References 99 publications

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

The hedgehog pathway in nonalcoholic fatty liver disease

A Recurrent Mosaic Mutation in SMO , Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

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