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.
Wong
Esther Sook Miin
ES
Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609.
Fong
Chee Wai
CW
Lim
Jormay
J
Yusoff
Permeen
P
Low
Boon Chuan
BC
Langdon
Wallace Y
WY
Guy
Graeme R
GR
D000818:Animals; D002460:Cell Line; D004331:Drosophila melanogaster; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008025:Ligases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C404992:Spry2 protein, rat; D025801:Ubiquitin; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D008025:Ligases; C067419:CBL protein, human