The Logic of EGFR/ErbB Signaling: Theoretical Properties and Analysis of High-Throughput Data

Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S. (2009) PLoS Comput Biol 5(8): e1000438.
The epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and [...]

Synergistic Drug-Cytokine Induction of Hepatocellular Death as an in vitro Approach for the Study of Inflammation-Associated Idiosyncratic Drug Hepatotoxicity

Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS, Griffith LG, Sorger PK, Tidor B, Xu JJ, Lauffenburger DA. (2009) Toxicol Appl Pharmacol 237(3): 317-30.
Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce [...]

Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis

Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK. (2009) Nature 459(7245): 428-32.
In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations. In mammalian cells, protein levels also vary and individual cells differ widely in their responsiveness to uniform physiological stimuli. In the case of apoptosis mediated by TRAIL (tumour [...]

Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling

Aldridge BB, Saez-Rodriguez J, Muhlich JL, Sorger PK, Lauffenburger DA. (2009) PLoS Comput Biol 5(4): e1000340.
When modeling cell signaling networks, a balance must be struck between mechanistic detail and ease of interpretation. In this paper we apply a fuzzy logic framework to the analysis of a large, systematic dataset describing the dynamics of cell signaling downstream [...]

Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data

Chen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK. (2009) Mol Syst Biol 5: 239.
The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how [...]

Microfluidics closes in on point-of-care assays

Sorger PK. (2008) Nat Biotechnol 26(12): 1345-6.
An integrated microfluidic device enables rapid detection of protein biomarkers in patient samples.
Routine assessment of biomarkers promises to transform many areas of medicine, from clinical trials, which will benefit from biomarkerbased segmentation of patient populations, to the diagnosis and treatment of complex disease. To add real value, biomarkers must be [...]

Modeling a Snap-Action, Variable-Delay Switch Controlling Extrinsic Cell Death

Albeck JG, Burke JM, Spencer SL, Lauffenburger DA, Sorger PK. (2008) PLoS Biol 6(12): e299.
When exposed to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL), a closely related death ligand and investigational therapeutic, cells enter a protracted period of variable duration in which only upstream initiator caspases are active. A subsequent and sudden transition [...]

Studying chromosome instability in the mouse

Foijer F, Draviam VM, Sorger PK. (2008) Biochim Biophys Acta 1786(1): 73-82.
Aneuploidy has long been recognized as one of the hallmarks of cancer. It nonetheless remains uncertain whether aneuploidy occurring early in the development of a cancer is a primary cause of oncogenic transformation, or whether it is an epiphenomenon that arises from a general [...]

Structural and functional dissection of Mif2p, a conserved DNA-binding kinetochore protein

Cohen RL, Espelin CW, De Wulf P, Sorger PK, Harrison SC, Simons KT. (2008) Mol Biol Cell 19(10): 4480-91.
Mif2p is the budding-yeast orthologue of the mammalian centromere-binding protein CENP-C. We have mapped domains of Saccharomyces cerevisiae Mif2p and studied the phenotyptic consequences of their deletion. Using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays, we [...]

Quantitative analysis of pathways controlling extrinsic apoptosis in single cells

Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK. (2008)  Mol Cell 30(1): 11-25.
Apoptosis in response to TRAIL or TNF requires the activation of initiator caspases, which then activate the effector caspases that dismantle cells and cause death. However, little is known about the dynamics and regulatory logic linking initiators and effectors. [...]