Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms.
Strict regulation of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway is essential for maintaining balanced growth in multi-cellular organisms. Several negative regulators of the pathway have been identified which include Sprouty proteins. Mammalian cells express four Sprouty isoforms (Sprouty1-4) in an ERK-dependent manner. In this study, we have examined the molecular mechanisms by which Sprouty proteins elicit their inhibitory effects on the RTK/ERK pathway, with special focus on the co-operation among Sprouty isoforms. The four mammalian Sprouty isoforms interact with each other, most probably to form hetero- as well as homo-oligomers through their C-terminal domains. Sprouty1 specifically interacts with Grb2, whereas Sprouty4 interacts with Sos1. Although any of the Sprouty isoforms by itself inhibits the fibroblast growth factor-2 (FGF-2)-induced activation of the ERK pathway significantly, hetero-oligomers show a more pronounced inhibitory activity. The hetero-oligomer formed between Sprouty1 and Sprouty4 exhibits the most potent inhibitory effect on ERK activation through its highly effective ability to suppress the association of Grb2-Sos1 complex with FRS2. The cooperative interactions observed among Sprouty isoforms could represent an advanced system that functions to regulate strictly the activation state of the RTK/ERK pathway in mammalian cells.
Ozaki
Kei-ichi
K
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan.
Miyazaki
Satsuki
S
Tanimura
Susumu
S
Kohno
Michiaki
M
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D041701:Swiss 3T3 Cells
D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D020033:Protein Isoforms; D020837:SOS1 Protein; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases