The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1.
Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1.
Nonami
Atsushi
A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Taketomi
Takaharu
T
Kimura
Akiko
A
Saeki
Kazuko
K
Takaki
Hiromi
H
Sanada
Takahito
T
Taniguchi
Koji
K
Harada
Mine
M
Kato
Reiko
R
Yoshimura
Akihiko
A
D048868:Adaptor Proteins, Signal Transducing; D021941:Caveolae / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047468:Immunoprecipitation; D008854:Microscopy, Electron; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases