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Submitted on May 16, 2003
Revised on June 25, 2003
Accepted on June 26, 2003

A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis

Kevin A. Janes, John G. Albeck, Lili X. Peng, Peter K. Sorger, Douglas A. Lauffenburger, and Michael B. Yaffe

Center for Cancer Research, Massachusetts Institute of Technology; E18-580, Cambridge, MA 02139

Corresponding Author: myaffe{at}mit.edu

To treat complex human diseases effectively, a systems-level approach is needed to understand the interplay of environmental cues, intracellular signals and cellular behaviors that underlie disease states. This approach requires high-throughput, multiplex techniques that measure quantitative temporal variations of multiple protein activities in the intracellular signaling network. Here, we describe a single microtiter-based format that simultaneously quantifies protein kinase activities in the phosphatidylinositol 3-kinase pathway (Akt), nuclear factor-kB pathway (IKK) and three core mitogen-activated protein kinase pathways (ERK, JNK1, MK2). These parallel high-throughput assays are stringently linear, redundantly specific, reproducible and sensitive compared to classical low-throughput techniques. When applied to a model of sepsis-induced colon epithelial apoptosis, this approach identified a late phase of Akt activity as a critical mediator of cell survival that quantitatively contributed to the efficacy of insulin as an anti-apoptotic cue. Thus, sampling parallel nodes in the intracellular signaling network identified part of the molecular mechanism underlying the efficacy of insulin in the treatment of human sepsis.


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