Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling.

Drosophila Sprouty (dSpry) was genetically identified as a novel antagonist of fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and Sevenless signalling, ostensibly by eliciting its response on the Ras/MAPK pathway. Four mammalian sprouty genes have been cloned, which appear to play an inhibitory role mainly in FGF- ...
mediated lung and limb morphogenesis. Evidence is presented herein that describes the functional implications of the direct association between human Sprouty2 (hSpry2) and c-Cbl, and its impact on the cellular localization and signalling capacity of EGFR. Contrary to the consensus view that Spry2 is a general inhibitor of receptor tyrosine kinase signalling, hSpry2 was shown to abrogate EGFR ubiquitylation and endocytosis, and sustain EGF-induced ERK signalling that culminates in differentiation of PC12 cells. Correlative evidence showed the failure of hSpry2DeltaN11 and mSpry4, both deficient in c-Cbl binding, to instigate these effects. hSpry2 interacts specifically with the c-Cbl RING finger domain and displaces UbcH7 from its binding site on the E3 ligase. We conclude that hSpry2 potentiates EGFR signalling by specifically intercepting c-Cbl-mediated effects on receptor down-regulation.
Mesh Terms:
Animals, Cell Line, Drosophila melanogaster, Endocytosis, Enzyme Activation, Epidermal Growth Factor, Fibroblast Growth Factors, Genes, Reporter, Humans, Ligases, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, ras Proteins
EMBO J.
Date: Sep. 16, 2002
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