Sprouty proteins: modified modulators, matchmakers or missing links?

Guy, Graeme R.; Jackson, Rebecca; Yusoff, Permeen; Chow, Soah Yee

doi:10.1677/joe-09-0110

Cited by 117 publications

(149 citation statements)

References 92 publications

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“…22 As for the mechanism by which Spry1 modulates the NFkB pathway, the lack of a universal mode of action of Spry proteins makes it difficult to explore candidate Owing to the absence of true conserved domains in Spry proteins, one strategy to investigate its mechanism of action has been to identify their binding partners, in a 'guiltyby-association' approach. 1 Following this reasoning, we envisage several potential mechanisms by which Spry1 could modulate the pathway. For example, dendritic cells lacking c-Cbl, a well-known Spry-binding partner, show increased cytokine secretion owing to augmented NFkB activity.…”

Section: Discussionmentioning

confidence: 99%

“…46 On the other hand, the adaptor protein CIN85, which also interacts with Spry1/2, is necessary for activation of the NFkB pathway in B lymphocytes upon BCR stimulation. 47 Finally, kinases of the Raf family including B-Raf interact with Spry1, 1 and Raf activation has been mechanistically linked to activation of the NFkB pathway. 48 In conclusion, there are many potential mechanisms by which Spry1 can induce NFkB activity that deserve further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood.…”

mentioning

confidence: 99%

“…Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others.…”

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Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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“…S4). SPRY1 is a negative regulator of the RAS-ERK pathway, which reportedly binds to SHP2 (encoded by PTPN11) and RAF1 through its cysteine-rich domain (CRD) and inhibits ERK activation via an as yet unclear mechanism (35). The nonsense variant encodes a truncated version of SPRY1 that retains its Casitas B-lineage lymphoma (CBL) tyrosine kinase-binding (TKB) motif but lacks the serine-rich domain and CRD; hence, the predicted SPRY1 truncation in NS17 might be functionally defective.…”

Section: Significancementioning

confidence: 99%

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

148

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Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed nextgeneration sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gainof-function alleles in Ras-like without CAAX 1 (RIT1) and mitogenactivated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that nextgeneration sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.human genetics | developmental diseases | whole exome sequencing | PTPN11 | RAS

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De novo 13q31.1–q32.1 interstitial deletion encompassing the miR‐17‐92 cluster in a patient with Feingold syndrome‐2

Tassano

Rocco

Signa

et al. 2013

American J of Med Genetics Pt A

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Sprouty proteins: modified modulators, matchmakers or missing links?

Cited by 117 publications

References 92 publications

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Next-generation sequencing identifies rare variants associated with Noonan syndrome

De novo 13q31.1–q32.1 interstitial deletion encompassing the miR‐17‐92 cluster in a patient with Feingold syndrome‐2

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