Spred is a Sprouty-related suppressor of Ras signalling.
Cellular proliferation, and differentiation of cells in response to extracellular signals, are controlled by the signal transduction pathway of Ras, Raf and MAP (mitogen-activated protein) kinase. The mechanisms that regulate this pathway are not well known. Here we describe two structurally similar tyrosine kinase substrates, Spred-1 and Spred-2. These two proteins contain a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of fibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppressing the MAP kinase pathway. Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essential in the differentiation of neuronal cells and myocytes. Expression of a dominant negative form of Spred and Spred-antibody microinjection revealed that endogenous Spred regulates differentiation in these types of cells. Spred constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation of MAP kinase by suppressing phosphorylation and activation of Raf. Spred may represent a class of proteins that modulate Ras-Raf interaction and MAP kinase signalling.
Wakioka
T
T
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Sasaki
A
A
Kato
R
R
Shouda
T
T
Matsumoto
A
A
Miyoshi
K
K
Tsuneoka
M
M
Komiya
S
S
Baron
R
R
Yoshimura
A
A
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins; D004330:Drosophila; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D004926:Escherichia coli; D019476:Insect Proteins / Q000737:chemistry* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D019476:Insect Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; C499021:Spred1 protein, rat; C433764:Spred2 protein, mouse; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C110486:sty protein, Drosophila; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins