Article

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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    • "The SPROUTYrelated enabled/vasodilator-stimulated phosphoprotein homology 1 domain-containing (SPRED) proteins (SPRED1 and 2) were first described by Wakioka et al (2001). SPREDs function by forming a complex with Raf and inhibiting activation of MEK (Wakioka et al, 2001; Bundschu et al, 2007). To date, there is very limited data on expression levels of SPRED1 and 2 in human cancers. "
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    ABSTRACT: Background: SPRED1 and 2 are key negative regulators of MAPK signalling in mammalian cells. Here, we investigate the expression and functional role of SPREDs in prostate cancer. Methods: A transcriptome bank of microdissected grade-specific primary cancers was constructed and interrogated for transcript expression of prostate cancer genes, known negative signalling regulators as well as SPRED1 and 2. The effect of SPRED2 manipulation was tested in in vitro assays. Results: In a panel of 5 benign glands and 15 tumours, we observed concomitant downregulation of the negative regulators SEF and DUSP1 in tumours with increasing Gleason grade. Profiling in the same cohorts revealed downregulation of SPRED2 mRNA in tumours compared with benign glands (P<0.05). By contrast, SPRED1 expression remained unchanged. This observation was further validated in two additional separate cohorts of microdissected tumours (total of n=10 benign and n=58 tumours) with specific downregulation of SPRED2 particularly in higher grade tumours. In functional assays, SPRED2 overexpression reduced ERK phosphorylation and inhibited prostate cancer cell proliferation and migration in response to different growth factors and full-media stimulation (P<0.001). Conversely, SPRED2 suppression by siRNA enhanced the mitogenic response to growth factors and full media (P<0.001). Conclusion: These data suggest first evidence that SPRED2 is downregulated in prostate cancer and warrants further investigation as a potential tumour-suppressor gene.
    British Journal of Cancer 11/2012; 108(3). DOI:10.1038/bjc.2012.507 · 4.82 Impact Factor
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    • "Interestingly, Spred1 and Spred2 were originally identified as c-Kit-interacting proteins (Wakioka et al. 2001). The role of the KBD in Spred function is not well understood, but it diverges among Spred family members; Spred3 lacks a key residue that is critical for the c-Kit interaction (Bundschu et al. 2007). Notably, c-Kit plays a central role in melanocyte biology. "
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    ABSTRACT: Mutations in the SPRED1 (Sprouty-related protein with an EVH [Ena/Vasp homology] domain 1) and NF1 (neurofibromatosis 1) genes underlie clinically related human disorders. The NF1-encoded protein neurofibromin is a Ras GTPase-activating protein (GAP) and can directly limit Ras activity. Spred proteins also negatively regulate Ras signaling, but the mechanism by which they do so is not clear. In the July 1, 2012, issue of Genes & Development, Stowe and colleagues (pp. 1421-1426) present evidence that Spred1 recruits neurofibromin to the membrane, where it dampens growth factor-induced Ras activity, providing a satisfying explanation for the overlapping features of two human diseases.
    Genes & development 07/2012; 26(14):1515-9. DOI:10.1101/gad.197434.112 · 12.64 Impact Factor
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    • "Knockout mice have deficits in hippocampaldependent learning and synaptic plasticity (Brems et al. 2007; Denayer et al. 2008), but the role of Spred proteins in forebrain progenitor cells has not yet been investigated. Spred1 inhibits the Ras–MAPK–ERK pathway downstream from NF1, at the level of Raf, interacting with its C-terminal catalytic domain (Sasaki et al. 2003; Bundschu et al. 2007). When overexpressed in a highly metastatic mouse osteosarcoma cell line, Spred1 can inhibit RhoAmediated cell motility and signal transduction (Miyoshi et al. 2004), but its role in neuronal migration has not been examined. "
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    ABSTRACT: Neural stem cells (NSCs) have great potential for self-renewal, which must be tightly regulated to generate appropriate cell numbers during development and to prevent tumor formation. The Ras-MAPK-ERK pathway affects mitogen-stimulated proliferation, and negative regulators are likely to be important for keeping self-renewal in check. Sprouty-related protein with an EVH1 domain (Spred1) is a recently discovered negative Ras-MAPK-ERK regulator linked to a neurofibromatosis 1 (NF-1)-like human syndrome; however, its role in CNS development has not been explored. We show that Spred1 is highly enriched in CNS germinal zones during neurogenesis. Spred1 knockdown increases NSC self-renewal and progenitor proliferation cell-autonomously, and overexpression causes premature differentiation. Surprisingly, Spred1 knockdown in vivo in the embryonic mouse forebrain frequently resulted in periventricular heterotopia, developmental abnormalities often associated with mutations in genes in the vesicular trafficking pathway that cause disruption of germinal zones and impair cell migration. In cortical progenitor cells, Spred1 localizes within distinct vesicles, indicating a potential role in transport. Spred1 knockdown gradually leads to disruption of the apical ventricular zone and loss of radial glia alignment. This impairs late neuronal migration, resulting in the formation of periventricular masses. Thus, Spred1 is critical for normal cortical development, as it modulates progenitor self-renewal/proliferation and helps maintain the integrity and organization of germinal zones.
    Genes & development 01/2010; 24(1):45-56. DOI:10.1101/gad.1839510 · 12.64 Impact Factor
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