<i>SPRED 1</i> Mutations in a Neurofibromatosis Clinic

Muram-Zborovski, Talia; Stevenson, David A.; Viskochil, David; Dries, David C.; Wilson, Andrew; Mao, Rong

doi:10.1177/0883073809359540

Cited by 34 publications

(31 citation statements)

References 22 publications

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“…The majority of reported Spred1 mutations produce a premature stop codon, resulting in C-terminally truncated protein products (Brems et al 2007;Messiaen et al 2009;Pasmant et al 2009;Spurlock et al 2009;Muram-Zborovski et al 2010;Denayer et al 2011;Laycock-van Spyk et al 2011;Spencer et al 2011). As the SPR domain has previously been reported to target Spred1 to the plasma membrane via interactions with phospholipids and caveolin-1 (Lim et al 2002;Nonami et al 2005), we surmised that the truncated mutants were unable to function as a result of mislocalization.…”

Section: Resultsmentioning

confidence: 97%

“…Initial experiments revealed that Spred1 mutations were loss-of-function mutations, incapable of inhibiting the Ras/MAPK pathway (Brems et al 2007). SPRED1 mutations account for at least 2% of the pathogenic mutations associated with patients clinically diagnosed with NF1 (Brems et al 2007;Messiaen et al 2009;Pasmant et al 2009;Spurlock et al 2009;Muram-Zborovski et al 2010;Denayer et al 2011;Laycock-van Spyk et al 2011;Spencer et al 2011).…”

mentioning

confidence: 99%

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A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Stowe

Mercado²,

Stowe³

et al. 2012

Genes Dev.

130

148

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The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome.

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Stowe

Mercado²,

Stowe³

et al. 2012

Genes Dev.

130

148

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“…The presence of cutaneous neurofibromas was documented upon time of examination. Given that some individuals with Legius syndrome fulfill the diagnostic criteria for NF1 based on pigmentary findings, children were screened for SPRED1 mutations as previously reported, 28 and individuals with SPRED1 mutations consistent with Legius syndrome were excluded.…”

Section: Methodsmentioning

confidence: 99%

Pediatric 25-hydroxyvitamin D concentrationsin neurofibromatosis type 1

Stevenson¹,

Viskochil²,

Carey³

et al. 2011

Journal of Pediatric Endocrinology and Metabolism

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Objective Low 25-hydroxyvitamin D (25OHD) concentrations have been associated with tumors and osteopenia/fractures in adults with neurofibromatosis type 1 (NF1). We report 25OHD concentrations in 109 children with NF1 and 218 age, sex, geographic location, and time-of-year matched controls. Methods Children with NF1 were recruited (n=109; 2–17yr), and clinical data and dual energy x-ray absorptiometry measurements obtained. 25OHD concentrations were measured in subjects and controls. Results More NF1 individuals (50%) were in the 25OHD insufficient/deficient range (<30ng/ml) compared to controls (36%) (p=0.0129). 25OHD concentrations were higher in individuals with neurofibromas after controlling for age (p=0.0393), and negatively associated with whole body subtotal bone mineral density (BMD) z-scores (p=0.0385). Conclusions More children with NF1 had 25OHD concentrations <30ng/ml, potentially due to increased pigmentation and/or decreased sunlight exposure. In contrast to adults, decreased 25OHD concentrations were not associated with neurofibromas, and there was not a positive association of 25OHD with BMD.

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“…Mutated genes responsible for the regulation of cell fate, genome integrity, and survival can lead to increased protein amplification and alter the tumor microenvironment, thus overactivating the pathway . These mutations can occur upstream in membrane receptor genes, such as epithelial growth factor receptor ( EGFR ), in signal transducers ( RAS ), regulatory partners ( Sprouty ), and downstream kinases that belong to the MAPK/ERK pathway itself ( BRAF ) (Fig. ) .…”

Section: Introductionmentioning

confidence: 99%

The MAPK pathway across different malignancies: A new perspective

Burotto

Chiou

Lee

et al. 2014

Cancer

791

597

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The MAPK/ERK pathway is activated by upstream genomic events and/or activation of multiple signaling events where information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, such as the AKT/m-TOR pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as BRAF. Currently approved for the treatment of melanoma, inhibitors of B-RAF kinase (BRAFi) are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize treatment of many tumor types. Therapies targeted toward MAPK/ERK components have variable response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, as different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs.

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SPRED 1 Mutations in a Neurofibromatosis Clinic

Cited by 34 publications

References 22 publications

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Pediatric 25-hydroxyvitamin D concentrationsin neurofibromatosis type 1

The MAPK pathway across different malignancies: A new perspective

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