Quantifying Signaling Networks: Pathway Crosstalk and Feedback Regulation

Historically, intracellular signal transduction has been characterized in terms of linear pathways, exemplified by the canonical MAPK cascades; e.g., the Ras → Raf → MEK → extracellular signal-regulated kinase (ERK) pathway in mammals. Yet it has been appreciated for some time that so-called signaling “pathways” are seldom activated or regulated in isolation. Indeed, it is well understood that they are simply dominant routes of regulation embedded in larger networks of interactions, including those between classically defined pathways (crosstalk) and those responsible for feedback regulation/reinforcement. But simply identifying the topology of the network is not enough; the magnitudes and dynamics of the interactions must be characterized, and this analysis must be performed for a spectrum of cell types and contexts. To do this, it is clear that a more quantitative approach is sorely needed.

Our approach in this area typically combines quantitative measurements and kinetic modeling, with the goal of elucidating the important crosstalk and feedback interactions in signaling networks mediated by growth factor and cytokine receptors. Publications selected from this line of research are listed below.

Related Publications

Herring LE, Grant KG, Blackburn K, Haugh JM, Goshe MB (2015). Development of a tandem affinity phosphoproteomic method with motif selectivity and its application in analysis of signal transduction networks. Journal of Chromatography B, 988: 166-174.

Rahman A, Haugh JM (2017). Kinetic modeling and analysis of the Akt/Mechanistic Target of Rapamycin Complex 1 (TORC1) signaling axis reveals cooperative, feedforward regulation. Journal of Biological Chemistry, 292: 2866-2872.

Rahman A, Haugh JM (2014). Deactivation of a negative regulator: a distinct signal transduction mechanism,
pronounced in Akt signaling. Biophysical Journal, 107: L29-L32.

Ahmed S, Grant KG, Edwards LE, Rahman A, Cirit M, Goshe MB, Haugh JM (2014). Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states. Molecular Systems Biology, 10: 718 (14 pages).

Cirit M, Grant KG, Haugh JM (2012). Systemic perturbation of the ERK signaling pathway by the proteasome inhibitor, MG132. PLOS ONE, 7: e50975.

Haugh JM (2012). Cell regulation: a time to signal, a time to respond. BioEssays, 34: 528-529 (Comment).

Cirit M, Haugh JM (2012). Data-driven modelling of receptor tyrosine kinase signalling networks quantifies receptor-specific potencies of PI3K- and Ras-dependent ERK activation. Biochemical Journal, 441: 77-85.

Cirit M, Haugh JM (2011). Quantitative models of signal transduction networks: How detailed should they be? Communicative & Integrative Biology, 4: 353-356 (Addendum Article).

Buhrman G, Kumar VSS, Cirit M, Haugh JM, Mattos C (2011). Allosteric modulation of Ras-GTP is linked to signal transduction through Raf kinase. Journal of Biological Chemistry, 286: 3323-3331.

Cirit M, Wang C-C, Haugh JM (2010). Systematic quantification of negative feedback mechanisms in the extracellular signal-regulated kinase (ERK) signaling network. Journal of Biological Chemistry, 285: 36736-36744.

Wang C-C, Cirit M, Haugh JM (2009). PI3K-dependent crosstalk interactions converge with Ras as quantifiable inputs integrated by Erk. Molecular Systems Biology, 5: art. 246 (11 pages).

Comfort KK, Haugh JM (2008). Combinatorial signal transduction responses mediated by interleukin-2 and -4 receptors in a helper TH2 cell line. Cellular and Molecular Bioengineering, 1: 163-172.

Monine MI, Haugh JM (2008). Signal transduction at point-blank range: analysis of a spatial coupling mechanism for pathway crosstalk. Biophysical Journal, 95: 2172-2182.

Kaur H, Park CS, Lewis JM, Haugh JM (2006). Quantitative model of Ras/phosphoinositide 3-kinase signalling cross-talk based on co-operative molecular assembly. Biochemical Journal, 393: 235-243.

Park CS, Schneider IC, Haugh JM (2003). Kinetic analysis of platelet-derived growth factor receptor/phosphoinositide 3-kinase/Aktsignaling in fibroblasts. Journal of Biological Chemistry, 278: 37064-37072.