Spred is a Sprouty-related suppressor of Ras signalling

Abstract

Cellular proliferation, and differentiation of cells in response to extracellular signals, are controlled by the signal transduction pathway of Ras, Raf and MAP (mitogen-activated protein) kinase. The mechanisms that regulate this pathway are not well known. Here we describe two structurally similar tyrosine kinase substrates, Spred-1 and Spred-2. These two proteins contain a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of fibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppressing the MAP kinase pathway. Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essential in the differentiation of neuronal cells and myocytes. Expression of a dominant negative form of Spred and Spred-antibody microinjection revealed that endogenous Spred regulates differentiation in these types of cells. Spred constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation of MAP kinase by suppressing phosphorylation and activation of Raf. Spred may represent a class of proteins that modulate Ras-Raf interaction and MAP kinase signalling.

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

“…In addition, our data are consistent with the finding that PD98059 is able to block the proliferation, migration and tube formation of endothelial cells in vitro (Wu et al, 2000;Srivastava et al, 2009). Intriguingly, the regulatory function of RKTG in angiogenesis is similar to that of Spred-1, which also functions as a negative regulator of Raf kinase by interfering with the phosphorylation and activation of Raf-1 (Wakioka et al, 2001). A study with micro-RNA miR-126 that targets Spred-1 has led to the discovery that miR-126 enhances angiogenesis by activation of ERK signaling .…”

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

“…Therefore, we speculated that a deficiency of Spred in hepatocytes causes hyperproliferative cell, leading to tumorigenicity. However, neither Spred-1 null mice nor Spred-2 null mice developed any tumors, which was probably due to the redundancy in the physiological function of Spred-1 and -2 because Spred-1 and -2 are coexpressed in various organs and have similar effect on ERK activity (Wakioka et al, 2001;Kato et al, 2003). In our study, expression levels of Spred-1 and -2 were simultaneously decreased in identical HCC tumors at a high rate (22/27:68%).…”

“…Moreover, constitutive overexpression of Spred as well as dominant-negative Ras (N17-Ras) enhanced the differentiation of C2C12 myoblastic cells with the decreased phosphorylation of ERK. In contrast, dominant-negative Spred (DC-Spred and DNSpred) did not differentiate myoblasts and maintained a higher level of ERK activity (Wakioka et al, 2001). In this study, we could not demonstrate whether Spred expression in HCC was associated with the degree of tumor differentiation because our samples mainly consisted of moderately differentiated HCC.…”

“…Recently we isolated Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain (Spred) as a negative regulator of the Ras/Raf-1/ERK pathway (Wakioka et al, 2001). The Spred family includes Spred-1, -2 and -3 .…”

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

“…Mediates receptor ubiquitylation [50,51] Retains Erk in the cytoplasm [8,52] Represses pointed-mediated transcription [53] Mediate IRS1/2 ubiquitylation and block access of substrates [54] Inhibits Ras-mediated Raf activation [55] Unknown Unknown [7] hypomorphic mutations of EGFR/LET-23 in C. elegans identified SLI-1 as a negative regulator of the EGFR signaling pathway [9]. In line with genetic evidence indicating that SLI-1 acts downstream to the receptor and upstream of Ras, c-Cbl, a mammalian ortholog of SLI-1, was shown to be rapidly phosphorylated and to complex with the EGFR following EGF stimulation [10].…”