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Published May 23, 2000 | Published
Journal Article Open

Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties

Abstract

In addition to preventing crosstalk among related signaling pathways, scaffold proteins might facilitate signal transduction by preforming multimolecular complexes that can be rapidly activated by incoming signal. In many cases, such as mitogen-activated protein kinase (MAPK) cascades, scaffold proteins are necessary for full activation of a signaling pathway. To date, however, no detailed biochemical model of scaffold action has been suggested. Here we describe a quantitative computer model of MAPK cascade with a generic scaffold protein. Analysis of this model reveals that formation of scaffold-kinase complexes can be used effectively to regulate the specificity, efficiency, and amplitude of signal propagation. In particular, for any generic scaffold there exists a concentration value optimal for signal amplitude. The location of the optimum is determined by the concentrations of the kinases rather than their binding constants and in this way is scaffold independent. This effect and the alteration of threshold properties of the signal propagation at high scaffold concentrations might alter local signaling properties at different subcellular compartments. Different scaffold levels and types might then confer specialized properties to tune evolutionarily conserved signaling modules to specific cellular contexts.

Additional Information

© 2000 by the National Academy of Sciences. Edited by Mark Ptashne, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved March 22, 2000 (received for review October 14, 1999). We thank B. J. Wold and three anonymous reviewers for discussion and critical review. This work was supported by Office of Naval Research Grant N00014–97-1–0293 and by a Jet Propulsion Laboratory grant to J.B. and P.W.S. (an investigator with the Howard Hughes Medical Institute), by a Sloan Research Fellowship to J.B., and by Burroughs–Wellcome Fund Computational Molecular Biology Postdoctoral Fellowship to A.L. This paper was submitted directly (Track II) to the PNAS office. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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August 21, 2023
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