Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways

Rubin, Chanan; Zwang, Yaara; Vaisman, Nora; Ron, Dina; Yarden, Yosef

doi:10.1074/jbc.m408308200

Cited by 39 publications

(34 citation statements)

References 41 publications

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“…kinase Src was implicated in Spry2 tyrosine phosphorylation [Li et al, 2004]; however, other tyrosine kinases may also be involved [Rubin et al, 2005]. SIAH2 may serve as an additional mechanism to regulate Spry2 levels and decrease the inhibitory effects of Spry2 on MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Sprouty2 stability by mammalian Seven‐in‐Absentia homolog 2

Nadeau

Toher

Yang

et al. 2006

J of Cellular Biochemistry

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Mammalian Sprouty (Spry) gene expression is rapidly induced upon activation of the FGF receptor signaling pathway in multiple cell types including cells of mesenchymal and epithelial origin. Spry2 inhibits FGFdependent ERK activation and thus Spry acts as a feedback inhibitor of FGF-mediated proliferation. In addition, Spry2 interacts with the ring-finger-containing E3 ubiquitin ligase, c-Cbl, in a manner that is dependent upon phosphorylation of Tyr55 of Spry2. This interaction results in the poly-ubiquitination and subsequent degradation of Spry2 by the proteasome. Here, we describe the identification of another E3 ubiquitin ligase, human Seven-in-Absentia homolog-2 (SIAH2), as a Spry2 interacting protein. We show by yeast two-hybrid analysis that the N-terminal domain of Spry2 and the ring finger domain of SIAH2 mediated this interaction. Co-expression of SIAH2 resulted in proteasomal degradation of Spry1, 2, and to a lesser extent Spry4. The related E3 ubiquitin-ligase, SIAH1, had little effect on Spry2 protein stability when coexpressed. Unlike c-Cbl-mediated degradation of Spry2, SIAH2-mediated degradation was independent of phosphorylation of Spry2 on Tyr55. Spry2 was also phosphorylated on Tyr227, and phosphorylation of this residue was also dispensable for SIAH2-mediated degradation of Spry2. Finally, co-expression of SIAH2 with Spry2 resulted in a rescue of FGF2-mediated ERK phosphorylation. These data suggest a novel mechanism whereby Spry2 stability is regulated in a manner that is independent of tyrosine phosphorylation, and provides an addition level of control of Spry2 protein levels.

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Section: Discussionmentioning

confidence: 99%

“…4A). Furthermore, mutation of an additional tyrosine on the carboxy terminus, Y227F, which was shown to also affect the ability of Spry2 to attenuate FGF-induced MAPK activation [Rubin et al, 2005], was also degraded by SIAH2. The data presented here suggest that Spry1 and Spry2 protein levels may be regu- Fig.…”

Section: Siah2-mediated Degradation Of Spry2 Ismentioning

confidence: 99%

Regulation of Sprouty2 stability by mammalian Seven‐in‐Absentia homolog 2

Nadeau

Toher

Yang

et al. 2006

J of Cellular Biochemistry

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“…These dichotomous activities may in part reflect differences in the regulation of Sprouty2 by different growth factors as Sprouty2 inhibits Erk activity induced by fibroblast growth factor (FGF) and vascular endothelial growth factor, whereas augmenting signaling from EGF by increasing EGFR protein stability (46 -48, 53, 54). Tyrosine phosphorylation of Sprouty2 may contribute to these differences in the function of Sprouty2 as FGF but not EGF induces phosphorylation at Tyr-227 of Sprouty2, and this phosphorylation is required for inhibition of FGF-induced Erk signaling (55). MCF-10A cells are dependent on EGF for survival, proliferation, and growth factor signaling and express high levels of EGFR (7,56).…”

Section: Discussionmentioning

confidence: 99%

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Grassian

Schafer

Brugge

2011

Journal of Biological Chemistry

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Epithelial cells are dependent on extracellular matrix (ECM) attachment for maintenance of metabolic activity and suppression of apoptosis. Here we show that loss of ECM attachment causes down-regulation of epidermal growth factor receptor (EGFR) and ␤1 integrin protein and mRNA expression and that ErbB2, which is amplified in 25% of breast tumors, reverses these effects of ECM deprivation. ErbB2 rescue of ␤1 integrin mRNA and protein in suspended cells is dependent on EGFR, however, the rescue of EGFR expression does not require ␤1 integrin. We show that there is a significant decrease in the stability of EGFR in ECM-detached cells that is reversed by ErbB2 overexpression. Rescue of both EGFR and ␤1 integrin protein by ErbB2 is dependent on Erk activity and induction of its downstream target Sprouty2, a protein known to regulate EGFR protein stability. Interestingly, expression of EGFR and ␤1 integrin protein is more dependent on Erk/ Sprouty2 in ECM-detached ErbB2-overexpressing cells when compared with ECM-attached cells. These results provide further insight into the ErbB2-driven anchorage independence of tumor cells and provide a new mechanism for regulation of EGFR and ␤1 integrin expression in ECM-detached cells.One of the hallmarks of tumor cells is the ability to survive without attachment to the extracellular matrix (ECM) 3 (1). Detachment of normal epithelial cells from ECM leads to metabolic impairment and induction of apoptotic death (anoikis) (2-5). However, tumor cells are generally able to survive without ECM attachment, a property known as "anchorage independence" (2, 3). This is believed to allow tumor cells to invade and proliferate outside their natural ECM niches. For example, one early feature of breast cancer is the proliferation of cells into the ECM-deficient hollow lumen of the glandular epithelium (6). These premalignant cells are able to survive despite the lack of contact to the basement membrane. Additionally, it is believed that anchorage independence is an important aspect of the metastatic process, both for survival in the vasculature and lymphatic system and also for survival in distant sites with altered matrix environments (2). Thus, elucidation of the mechanisms responsible for tumor cell anchorage independence is critical for understanding of the tumorigenic processes and may lead to identification of novel drug targets.ECM detachment of mammary epithelial cells results in a decrease of growth factor signaling through the Mek/Erk and PI3K/Akt pathways (2, 4, 5, 7). This leads to decreased cell viability, both through the induction of anoikis and through a caspase-independent metabolic impairment (2, 4). We have previously found that decreased Erk activation in ECM-detached cells leads to increased expression of the pro-apoptotic protein, Bim (7-9). In addition, the lack of Akt signaling in the ECM-detached cells results in a dramatic decrease in glucose uptake and ATP levels, causing a severe energy deficiency (4). Therefore, survival of mammary epithelial cells under ECM-de...

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“…For example, Spry1 is phosphorylated after FGF and platelet-derived growth factor stimulation, Spry2 is phosphorylated following EGF and FGF stimulation, whereas Spry4 is not phosphorylated following exposure to any of these growth factors. More recently, Rubin and co-workers (38) demonstrated that different tyrosine residues found in the C-terminal domain of Spry2 were phosphorylated in distinct patterns depending on the stimulus (either EGF or FGF), thus imparting a discriminatory role on this domain. Spry differences in function may also vary from cell to cell depending on which components of the RTK signalosome are present and activated by different ligands (3).…”

Section: Cooperative Inhibitorsmentioning

confidence: 99%

A Functional Interaction between Sprouty Proteins and Caveolin-1

Cabrita¹,

Jäggi

Widjaja

2006

Journal of Biological Chemistry

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Growth factor-mediated signal transduction cascades can be regulated spatio-temporally by signaling modulators, such as Sprouty proteins. The four mammalian Sprouty family members are palmitoylated phosphoproteins that can attenuate or potentiate numerous growth factor-induced signaling pathways. Previously, we have shown that Sprouty-1 and Sprouty-2 associate with Caveolin-1, the major structural protein of caveolae. Like Sprouty, Caveolin-1 inhibits growth factor-induced mitogen-activated protein kinase activation. Here, we demonstrate that all four mammalian Sprouty family members physically interact with Caveolin-1. The C terminus of Caveolin-1 is the major Sprouty-binding site, whereas Sprouty binds Caveolin-1 via its conserved C-terminal domain. A single point mutation in this domain results in loss of Caveolin-1 interaction. Moreover, we demonstrate that the various Sprouty isoforms differ dramatically in their cooperation with Caveolin-1-mediated inhibition of mitogen-activated protein kinase activation and that such cooperation is also highly dependent on the type of growth factor investigated and on cell density. Together, the data suggest that the Sprouty/Caveolin-1 interaction modulates signaling in a growth factor-and Sprouty isoform-specific manner.

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Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways

Cited by 39 publications

References 41 publications

Regulation of Sprouty2 stability by mammalian Seven‐in‐Absentia homolog 2

Regulation of Sprouty2 stability by mammalian Seven‐in‐Absentia homolog 2

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

A Functional Interaction between Sprouty Proteins and Caveolin-1

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