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Douglas Lauffenburger MIT Department of Biology
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Douglas Lauffenburger
Douglas Lauffenburger
Professor of Biological Engineering and Biology
Ph.D. 1979, University of Minnesota
Room 56-341
Phone: (617) 252-1629
Email: lauffen at mit.edu
Lauffenburger Lab Home Page


It is becoming increasingly apparent that to more fully understand how cells operate as integrated molecular systems, an intimate combination of quantitative experiment and computational modeling is required. This is clearly the case for the complex receptor-mediated signaling networks activated by growth factors, cytokines, and extracellular matrix. Accordingly, we are attempting to develop multi-variable, multi-parametric 'systems biology' measurement and analysis methodologies useful for investigating signaling networks and cell functions they regulate.

Research Summary
The epidermal growth factor receptor [EGFR] system provides one especially attractive paradigm for this quantitative systems biology approach, because of the substantial amount of information regarding its key components, its highly conserved evolutionary nature, and its strong relevance to development, physiology, and disease. A central aim of our laboratory is to generate a fusion of experiment and modeling to address a variety of questions about how the EGFR system operates as a highly modulated dynamic 'circuit' to help regulate a variety of important cell functions including survival, proliferation, and migration. These studies are connected to analogous investigations across a broader context involving regulatory signaling networks activated by other growth factors, cytokines, and matrix components as well as environmental stresses, with cancer as a major application area. Examples of current project areas include the following.

Autocrine Ligand/Receptor Loops: An intriguing feature of the EGFR system is that it commonly operates in autocrine fashion, with its family of ligands (including EGF, TGFa, HB-EGF, and amphiregulin) being synthesized as transmembrane precursors whose release is governed by regulated proteolytic cleaveage at specific sites. The extent to which subsequently released ligand is self-captured by the producing cell or a proximal neighbor as opposed to escaping to distal tissue regions determines the strength of resulting signaling via EGFR-mediated pathways. The molecular and cellular properties governing autocrine ligand capture are poorly understood, so we are attempting to elucidate and manipulate them. Additionally, we are trying to discern what physiological roles EGFR autocrine loops play in embryonic development and adult tissue organization and homeostasis, and how pathological dysregulation can occur related to cancer or other hypertrophic diseases. At present attention is focused on mammary and lung epithelial cells.

Endocytic Trafficking and Signaling: Activation of diverse signaling pathways downstream of EGFR can vary with the location of the receptor/ligand complex, as modulated by endocytic trafficking processes of internalization and recycling. Consequently, factors which influence EGFR trafficking can substantially alter signaling network activity. This effect can have serious implications for resulting cell behavorial functions because certain functions, such as motility, depend to greater or lesser degrees on the activation levels of different EGFR-induced pathways. As one important example, expression of a second member of the EGFR family, HER2 (or erbB2), is strongly correlated with invasive tumor progression in carcinomas. Thus, we are exploring the possibility that a significant portion of this dysregulation of epithelial cell proliferation and migration behavior arises from altered EGFR trafficking due to HER2/EGFR interactions, with a focus on mammary and prostate epithelial cells.

Regulation of Cell Migration: Migration is a behavioral cell function important in a wide spectrum of physiological, pathological, and technological problems, e.g., organ development, tissue organization, inflammatory and immune responses, tumor invasion and metastasis, wound healing, and biomaterials colonization. This cell behavior requires exquisite coordination of a number of dynamic biophysical processes including membrane extension, cell/matrix adhesion, and cytoskeletal force generation and transmission, which are regulated by signals from growth factor and matrix receptors. We are especially interested in biophysical process regulation by EGFR-mediated signals as they synergize with those from extracellular matrix components such as fibronectin and collagen. Our recent efforts have focused on two EGFR-activated pathways that appear to be specific to motogenic cell responses, apart from mitogenic responses, in fibroblasts and epithelial cells, rendering them promising targets for cancer therapeutics: PLCg, a governor of cytoskeleton/membrane interactions, and calpain, actually a family of intracellular cysteine proteases whose enyzmatic activities are modulated by phosphorylation as well as calcium-binding. Intriguingly, activation of both of these pathways downstream of EGFR appears to be spatially-restricted in manner enabling the asymmetric force transmission from cytoskeleton to extracellular matrix necessary for translating intracellular forces into cell locomotion. We are accordingly testing whether inhibition of these pathways may be useful for reducing invasiveness and metastatic capability of breast and prostate carcinoma cells.

Regulation of Cell Death/Survival Decisions: Programmed cell death, or apoptosis, is similarly involved in various problem areas. The execution phase of apoptosis, largely carried out by the caspases, is primarily governed by upstream signaling networks integrating inputs from potentially competing death and survival stimuli, which comprise cytokines, growth factors, extracellular matrix, and environmental insults such as radiation and chemical toxins. We are attempting to quantitatively characterize the dependence of execution phase operation on a dynamic set of signaling network activities, with emphasis on certain EGFR-mediated pathways potentially serving in key pro-survival roles. As part of this effort we are developing high-throughput quantitative assays for specific kinase activities on particular downstream substrates, and are applying a battery of computational modeling (e.g., Bayesian, vector state-space, and physico-chemical kinetic) methodologies to analyze relationships elucidating how signaling network activities downstream of pro-death and pro-survival stimuli may govern cell death-vs-survival responses.

Selected Publications
Sachs, K., O. Perez, D. Pe'er, D.A. Lauffenburger, and G.P. Nolan. Causal Protein Signaling Networks Derived From Multiparameter Single-Cell Data, Science 308: 523-529 (2005).

Hautaniemi, S., S. Kharait, A. Iwabu, A. Wells, and D.A. Lauffenburger. Modeling of Signal-Response Cascades using Decision Tree Analysis, Bioinformatics 21: 2027-2035 (2005).

Hendriks, B.S., G. Orr, A. Wells, H.S. Wiley, and D.A. Lauffenburger. Parsing ERK Activation Reveals Quantitatively Equivalent Contributions from EGFR and HER2 in Human Mammary Epithelial Cells, J. Biol. Chem. 280: 6157-6169 (2005).

Janes, K.A., J. R. Kelly, S. Gaudet, J.G.Albeck, P.K. Sorger, and D.A. Lauffenburger. Cue-Signal-Response Analysis of TNF-Induced Apoptosis by Partial Least Squares Regression of Dynamic Multi-Variate Signaling Network Measurements, J. Comp. Biol. 11: 544-561 (2004).

Prudhomme, W., K. Duggar, G.Q. Daly, P.W. Zandstra, and D.A. Lauffenburger. Multi-Variate Proteomic Analysis of Murine Embryonic Stem Cell Self-Renewal vs Differentiation Behavior, Proc. Natl. Acad. Sci. USA 101: 2900-2905 (2004).

Wiley, H.S., S.Y. Shvartsman, and D.A. Lauffenburger. Computational Modeling of the EGF Receptor System: A Paradigm for Systems Biology, Trends Cell Biol. 13: 43-50 (2003).

Search PubMed for Lauffenburger Lab publications; also see Lab website for a complete list.




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