Getting a first clue about SPRED functions

Abteilung Biochemie und Molekulare Biologie, Universität Ulm, Ulm, Germany.
BioEssays (Impact Factor: 4.84). 09/2007; 29(9):897-907. DOI: 10.1002/bies.20632
Source: PubMed

ABSTRACT Spreds form a new protein family with an N-terminal Enabled/VASP homology 1 domain (EVH1), a central c-Kit binding domain (KBD) and a C-terminal Sprouty-related domain (SPR). They are able to inhibit the Ras-ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen-induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds help together with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions.

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    ABSTRACT: Objectives: Angiogenesis, a crucial component of wound healing, follows a branched tubular development and is regulated by signals received by receptor tyrosine kinases (RTKs). Mammalian Sprouty (Spry) proteins are known to function by specifically antagonizing the activation of the mitogen-activated protein kinase (MAPK) signaling pathway by RTKs, especially vascular endothelial growth factor (VEGF) receptors. The purpose of this research is to determine the role of Sprouty 2 in the regulation of wound angiogenesis. Methods: To examine Spry2 levels during wound healing in vivo, excisional dermal wounds were made on the dorsum of 6-to-8 week-old female FVB-strain mice using 3-mm punch-biopsy instruments; wound samples were harvested and analyzed for mRNA expression of Spry2 at 0, 1, 3, 5, 7, 10, 14, 21, 28 days post-injury using Real-Time PCR and GAPDH as endogenous control (n=5). In another study, gel containing Spry2, negative dominant Y55F mutant of Spry2, or green fluorescent protein (GFP) control was applied topically to healing wounds 5 days post-injury; wound samples were harvested 10 days post-injury and analyzed for vascularity using PECAM-1 staining (n=3). Results: mRNA expression quantification experiments showed that Spry2 mRNA levels increase after day 5 and peak at day 14 post-injury, a time when vascular regression occurs (p<0.05). Western blot protein analyses confirmed the general pattern of Spry2 expression. Quantification of positive PECAM-1 staining showed a decrease in blood vessel formation in Spry2 treated mice compared to the GFP control group, whereas mice treated with the Y55F mutant exhibited a relative increase in vascularity. Conclusion: Spry2 production follows a defined pattern that parallels the pattern of wound angiogenesis, with peak Spry2 levels occurring during active vascular regression. Application of exogenous Spry2 to wounds inhibits angiogenesis. Taken together, the results suggest that Spry2 down-regulates vascularity and/or vascular branching during wound angiogenesis. R01 GM50875 (LAD); T32 DE018381 (LAD,MW)
    IADR General Session 2009; 04/2009
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    ABSTRACT: Background Large Tumor Suppressor 2(LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer.The aim of this study is to explore the association of aberrant LATS2expression with EGFRmutation and survival in lung adenocarcinoma(AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into fourEGFR wild-type(WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results Fifty resected lung AD were included(M:F = 23:27,Smokers:non-smokers = 19:31,EGFRmutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend.LATS2 mRNA level was found to be a significant independent predictor for survival status(Disease-free survival RR = 0.217; p = 0.003; Overall survival RR = 0.238; p = 0.036).siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LAST2 expression, discriminatory modulation of Akt signaling between EGFRwild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baselinep53 levels. Conclusions LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.
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    ABSTRACT: Background: Pluripotency, self-renewal, and differentiation are special features of embryonic stem (ES) cells, thereby providing valuable perspectives in regenerative medicine. Developmental processes require a fine-tuned organization, mainly regulated by the well-known JAK/STAT, PI3K/AKT, and ERK/MAPK pathways. SPREDs (Sprouty related proteins with EVH1 domain) were discovered as inhibitors of the ERK/MAPK signaling pathway, whereas nothing was known about their functions in ES cells and during early differentiation, so far. Results: We generated SPRED1 and SPRED2 overexpressing and SPRED2 knockout murine ES cells to analyze the functions of SPRED proteins in ES cells and during early differentiation. Overexpression of SPREDs increases significantly the self-renewal and clonogenicity of murine ES cells, whereas lack of SPRED2 reduces proliferation and increases apoptosis. During early differentiation in embryoid bodies, SPREDs promote the pluripotent state and inhibit differentiation whereby mesodermal differentiation into cardiomyocytes is considerably delayed and inhibited. LIF- and growth factor-stimulation revealed that SPREDs inhibit ERK/MAPK activation in murine ES cells. However, no effects were detectable on LIF-induced activation of the JAK/STAT3, or PI3K/AKT signaling pathway by SPRED proteins. Conclusions: We could show that SPREDs promote self-renewal and inhibit mesodermal differentiation of murine ES cells by selective suppression of the ERK/MAPK signaling pathway in pluripotent cells. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Developmental Dynamics 02/2015; 244(4). DOI:10.1002/dvdy.24261 · 2.67 Impact Factor