Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops.
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.
Rubin
Chanan
C
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Litvak
Vladi
V
Medvedovsky
Helena
H
Zwang
Yaara
Y
Lev
Sima
S
Yarden
Yosef
Y
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005246:Feedback; D006801:Humans; D006868:Hydrolysis; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C404992:Spry2 protein, rat; D025801:Ubiquitin; D014443:Tyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human