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  • Title: Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops.
    Author: Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y.
    Journal: Curr Biol; 2003 Feb 18; 13(4):297-307. PubMed ID: 12593795.
    Abstract:
    BACKGROUND: Growth factors and their receptor tyrosine kinases play pivotal roles in development, normal physiology, and pathology. Signal transduction is regulated primarily by receptor endocytosis and degradation in lysosomes ("receptor downregulation"). c-Cbl is an adaptor that modulates this process by recruiting binding partners, such as ubiquitin-conjugating enzymes. The role of another group of adaptors, Sprouty proteins, is less understood; although, studies in insects implicated the founder protein in the negative regulation of several receptor tyrosine kinases. RESULTS: By utilizing transfection of living cells, as well as reconstituted in vitro systems, we identified a dual regulatory mechanism that combines human Sprouty2 and c-Cbl. Upon activation of the receptor for the epidermal growth factor (EGFR), Sprouty2 undergoes phosphorylation at a conserved tyrosine that recruits the Src homology 2 domain of c-Cbl. Subsequently, the flanking RING finger of c-Cbl mediates poly-ubiquitination of Sprouty2, which is followed by proteasomal degradation. Because phosphorylated Sprouty2 sequesters active c-Cbl molecules, it impedes receptor ubiquitination, downregulation, and degradation in lysosomes. This competitive interplay occurs in endosomes, and it regulates the amplitude and longevity of intracellular signals. CONCLUSIONS: Sprouty2 emerges as an inducible antagonist of c-Cbl, and together they set a time window for receptor activation. When incorporated in signaling networks, the coupling of positive (Sprouty) to negative (Cbl) feedback loops can greatly enhance output diversification.
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