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OSBP Is a Cholesterol-Regulated Scaffolding Protein in Control of ERK1/2 Activation
Ping-yuan Wang,
Jian Weng,
Richard G. W. Anderson*
Abstract:
Oxysterol-binding protein (OSBP) is the founding member of afamily of sterol-binding proteins implicated in vesicle transport,lipid metabolism, and signal transduction. Here, OSBP was foundto function as a cholesterol-binding scaffolding protein coordinatingthe activity of two phosphatases to control the extracellularsignal–regulated kinase (ERK) signaling pathway. CytosolicOSBP formed a 440-kilodalton oligomer with a member of the PTPPBSfamily of tyrosine phosphatases, the serine/threonine phosphatasePP2A, and cholesterol. This oligomer had dual specific phosphataseactivity for phosphorylated ERK (pERK). When cell cholesterolwas lowered, the oligomer disassembled and the level of pERKrose. The oligomer also disassembled when exposed to oxysterols.Increasing the amount of OSBP oligomer rendered cells resistantto the effects of cholesterol depletion and decreased the basallevel of pERK. Thus, cholesterol functions through its interactionwith OSBP outside of membranes to regulate the assembly of anoligomeric phosphatase that controls a key signaling pathwayin the cell.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390–9039, USA.
* To whom correspondence should be addressed. E-mail: richard.anderson{at}utsouthwestern.edu
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440-kilodalton oligomer with a member of the PTPPBS family of tyrosine phosphatases, the serine/threonine phosphatase PP2A, and cholesterol. This oligomer had dual specific phosphatase activity for phosphorylated ERK (pERK). When cell cholesterol was lowered, the oligomer disassembled and the level of pERK rose. The oligomer also disassembled when exposed to oxysterols. Increasing the amount of OSBP oligomer rendered cells resistant to the effects of cholesterol depletion and decreased the basal level of pERK. Thus, cholesterol functions through its interaction with OSBP outside of membranes to regulate the assembly of an oligomeric phosphatase that controls a key signaling pathway in the cell. 
