Professor of Biological Engineering
"The focus of research in our laboratory is the identification of protein phosphorylation events regulating signal transduction cascades associated with cancer and other biological processes. With our mass spectrometry-based technology, identification of protein phosphorylation occurs on a global scale, allowing for mapping of complex signal transduction cascades in a variety of biological samples. Initially, we are applying this technology to cancer, including the analysis of human cell lines and other model systems, and extending through to the analysis of human clinical samples. Elucidation of signal transduction cascades involved in oncogenesis, cancer progression, and metastasis will generate both novel drug targets and a host of biological markers, allowing for early diagnosis and tracking of cancer progression. We will pursue a variety of other applications, including mapping the phosphorylation events associated with DNA damage response and cell cycle regulation."
Forest White’s research seeks to develop a detailed understanding of the signaling networks that allow cells to respond to external stimuli. Receptors on the surface of cells interact with molecules, or ligands, in the extracellular environment, and the receptors must then communicate information to the inside of a cell. The most common way to transmit these signals is by covalent modification of target proteins within the signaling pathway, most often adding a phosphate group (phosphorylation) or removing a phosphate group. Phosphorylation is performed by enzymes called “kinases,” and dephosphorylation is performed by “phosphatases.” Both failure and overactivity of kinases and phosphatases can lead to human diseases such as cancer, diabetes, and autoimmune disorders. Most studies of these signaling networks have been constrained by the need to focus on a single enzyme or phosphorylation site. White has developed a new methodology, taking advantage of mass spectrometry, to examine large portions of the networks at once, while still being able to examine individual sites. White is using this technology to study the mechanisms underlying the progression of breast, prostate, brain, and lung cancers. The goal of White’s research is to deepen the understanding of how cells respond to their environment, as well as to develop new ways to detect malfunctions in the cellular networks and develop corresponding therapies. Dr. White is a professor of biological engineering at MIT. He received his Ph.D. from Florida State University in 1997.
The goal of research in the White lab is to understand how protein phosphorylation-mediated signaling networks drive biological responses to cellular stimulation. Biological systems are presented with a variety of different cues, including growth factors, cytokines, over-expression, mutation, or knock-down of components in the network. These systems then process this information through signaling networks, ultimately resulting in altered biological behavior including proliferation, migration, invasion, and altered gene and protein expression. Quantification of the signaling networks which result from each of these cues and drive the corresponding biological response should provide key information regarding the mechanism by which the biological system is regulated. A protein may have multiple phosphorylation sites which control different biological functions and show unique phosphorylation dynamics. A site-specific high-resolution map of the signaling network, with associated temporal dynamics, will enable improved computational modeling of the systems and provide predictive power for more effective targeted interventions in aberrant signaling networks.
Within this framework, a significant fraction of research in the group is centered on the Epidermal Growth Factor Receptor (EGFR) signaling network. Specifically, we are interested in quantifying site-specific temporal dynamics of protein phosphorylation within the EGFR network under a variety of conditions while monitoring changes in the network induced by perturbations at the ligand and receptor level. The goal of this research is understand the biology downstream of EGFR activation and mutation, two events common to many human cancers. ?
Much of the work in the lab has a translational focus, aimed at understanding signaling network regulation and dysregulation in human disease, with the ultimate goal of identifying critical nodes in the network that may allow for intervention in the disease process. We are currently focused on studying signaling networks in several different cancer sub-types, including glioblastoma, breast, and lung cancers, as well as signaling networks underlying development and progression of Type I and Type II diabetes.
To interrogate the signaling networks in these diverse biological systems, we use state of the art hybrid mass spectrometers coupled with stable-isotope labeling, affinity chromatography, and LC-MS/MS to quantify temporal dynamics of protein post-translational modifications on hundreds of proteins simultaneously with site-specific resolution. This quantitative signaling network data is then used to build computational models, including those models in which the signaling data is correlated with quantitative biological phenotypic data. Collaborative work is on-going with the Lauffenburger, Tidor, and Fraenkel labs within the Biological Engineering Department to build improved methods of computational analysis and modeling of signaling networks. These models will then be used to predict biological and signaling network responses to additional perturbations to the system.
White FM, “The potential cost of high-throughput proteomics” Sci. Signal. 4, pe8 (2011)
Huang PH, Miraldi ER, Xu AM, Kundukulam VA, Del Rosario AM, Flynn RA, Cavenee WK, Furnari FB, White FM. “Phosphotyrosine signaling analysis of site-specific mutations on EGFRvIII identifies determinants governing glioblastoma cell growth.” Mol Biosyst. 15, 1227-1237 (2010)
Joughin B.A.; Naegle K.M.; Huang P.H.; Yaffe M.B.; Lauffenburger D.A.; White F.M. “An integrated comparative phosphoproteomic and bioinformatic approach reveals a novel class of MPM-2 motifs upregulated in EGFRvIII-expressing glioblastoma cells.” Mol Biosyst. 5, 59-67 (2009)
Huang, P.H.; Mukasa, A.; Bonavia, R.; Flynn, R.A.; Brewer, Z.E.; Cavenee, W.K.; Furnari, F.B.; White, F.M. “Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma” Proc. Nat. Acad. Sci. 104, 12867-12872 (2007)
Wolf-Yadlin, A.; Hautaniemi, S.; Lauffenburger, D.A.; White, F.M. “Multiple reaction monitoring for robust quantitative analysis of cellular signaling networks” Proc. Nat. Acad. Sci. 104, 5860-5865 (2007)
Wolf-Yadlin, A.; Kumar, N.; Zhang, Y.; Hautaniemi, S.; Zaman, M.; Kim, H.-D.; Grantcharova, V.; Lauffenburger, D.A.; White, F.M. “Quantitative Phosphoproteomic Analysis of HER2-overexpression effects on Cell Signaling Networks governing proliferation and migration” Mol. Systems Biol. 2, 54 (2006)