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.
"There are many feedback loops within RTK pathways, as well as cross talk between different pathways, making the net signaling outcome an integrated result of all these components. RTK pathways are regulated by a series of endogenous antagonists that fine-tune the signaling, including the Sprouty and Spred family members23. "
[Show abstract][Hide abstract] ABSTRACT: Sprouty (Spry) genes encode negative regulators of receptor tyrosine kinase (RTK) signaling, which plays important roles in human embryonic stem cells (hESCs). SPRY2 and SPRY4 are the two most highly expressed Sprouty family members in hESCs, suggesting that they may influence self-renewal. To test this hypothesis, we performed siRNA-mediated knock down (KD) studies. SPRY2 KD resulted in increased cell death and decreased proliferation, whereas SPRY4 KD enhanced survival. In both cases, after KD the cells were able to differentiate into cells of the three germ layers, although after SPRY2 KD there was a tendency toward increased ectodermal differentiation. SPRY2 KD cells displayed impaired mitochondrial fusion and cell membrane damage, explaining in part the increased cell death. These data indicate that Sprouty genes regulate pathways involved in proliferation and cell death in hESCs.
"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. "
[Show abstract][Hide abstract] 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.
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.
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).
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 · 4.84 Impact Factor
"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. "
[Show abstract][Hide abstract] 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 · 10.80 Impact Factor
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