The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1

Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Genes to Cells (Impact Factor: 2.81). 10/2005; 10(9):887-95. DOI: 10.1111/j.1365-2443.2005.00886.x
Source: PubMed


Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1.

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Available from: Takahito Sanada, Oct 29, 2014
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    • "Likewise, it remains to be determined if Spry1 plays an inhibitory role in all T cell subsets. While the precise role of Spry1 in these systems has yet to be identified, another member of the sprouty family Sprouty-related Ena/VASP homology 1-domain-containing protein 1 (Spred1) has been shown to inhibit IL-3-induced MAP-kinase activation in hematopoietic cells [17]. Additionally, Spred1 has been shown to negatively regulate IL-5-induced eosnophilia in a mouse model of asthma [18]. "
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    • "The KBD is involved but not essential in ERK suppression [Nonami et al., 2004; Wakioka et al., 2001]. Spred1 localizes in the lipid raft/caveolar fraction by virtue of its C-terminal part (SPR) and interacts with caveolin [Nonami et al., 2005]. Spred1 expression has an effect on the actin cytoskeleton via its N-terminal EVH-1 and C-terminal SPR domain. "
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    • "The majority of reported Spred1 mutations produce a premature stop codon, resulting in C-terminally truncated protein products (Brems et al. 2007; Messiaen et al. 2009; Pasmant et al. 2009; Spurlock et al. 2009; Muram-Zborovski et al. 2010; Denayer et al. 2011; Laycock-van Spyk et al. 2011; Spencer et al. 2011). As the SPR domain has previously been reported to target Spred1 to the plasma membrane via interactions with phospholipids and caveolin-1 (Lim et al. 2002; Nonami et al. 2005), we surmised that the truncated mutants were unable to function as a result of mislocalization . To test this hypothesis, we artificially localized the Spred1 C-terminal truncation mutant (M266fsX4) to the membrane by fusing it to the membrane targeting CAAX motif of Kras4B (Fig. 2A). "
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