The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins.
Signal transduction through epidermal growth factor receptors (EGFRs) is essential for the growth and development of multicellular organisms. A genetic screen for regulators of EGFR signaling has led to the identification of Sprouty, a cell autonomous inhibitor of EGF signaling that is transcriptionally induced by the pathway. However, the molecular mechanisms by which Sprouty exerts its antagonistic effect remain largely unknown. Here we have used transient expression in human cells to investigate the functional properties of human Sprouty (hSpry) proteins. Ectopically expressed full-length hSpry1 and hSpry2 induce the potentiation of EGFR-mediated mitogen-activated protein (MAP) kinase activation. In contrast, truncation mutants of hSpry1 and hSpry2 containing the highly conserved carboxyl-terminal cysteine-rich domain inhibit EGF-induced MAP kinase activation. The potentiating effect of the full-length hSpry2 proteins on EGF signaling is mediated by the amino-terminal domain and results from the sequestration of c-Cbl, which in turn leads to the inhibition of EGFR ubiquitination and degradation. These results indicate that hSpry2 can function both as a negative and positive regulator of EGFR-mediated MAP kinase signaling in a domain-dependent fashion. A dual function of this kind could provide a mechanism for achieving proper balance between the activation and repression of EGFR signaling.
Egan
James E
JE
Department of Molecular Genetics and Microbiology and Graduate Program in Molecular Pharmacology, State University of New York, Stony Brook, NY 11794-5222, USA.
Hall
Amy B
AB
Yatsula
Bogdan A
BA
Bar-Sagi
Dafna
D
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003545:Cysteine / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D029721:Drosophila Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D018076:DNA, Complementary; D029721:Drosophila Proteins; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C485561:SPRY2 protein, human; D025801:Ubiquitin; C110486:sty protein, Drosophila; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; C067419:CBL protein, human; D003545:Cysteine