Haugh Lab Research

In mammalian cell biology, the ongoing challenge is to bridge the gaps in our understanding of processes at the molecular, cellular, and tissue levels. Central to this hierarchy of biological complexity is the field of signal transduction, which deals with the biochemical mechanisms by which cells respond to external stimuli. Intracellular signaling processes control the growth, survival, differentiation and migration of cells in normal physiological contexts, and defects in signaling form the molecular basis for cancer, immune system disorders, and other diseases. Since 2000, the Haugh Laboratory has implemented a quantitative approach that combines biochemical measurements, live-cell fluorescence microscopy, and computational modeling to study signal transduction through analysis of its kinetics and spatial patterns in cells.

A cell’s ability to sense, respond, and adapt to external signals is largely mediated by receptor proteins expressed on the cell surface. Receptors are bifunctional in that they are responsible for both molecular recognition of extracellular ligands and signal transduction through interactions with intracellular enzymes and adaptor proteins. Each cell’s repertoire of cell surface receptors determines which ligands it responds to, and once activated, most receptors plug into a common set of signal transduction pathways.

Common signaling pathways accessed by cell surface receptors. The arrow diagram is organized both horizontally and vertically as follows. From left to right, the diagram depicts the Ras/MAPK pathway, lipid modification pathways (PI3K and PLC), and activation of Rho-family GTPases. From top to bottom, the diagram depicts receptors, adaptors, receptor-proximal enzymes, membrane-anchored lipids and proteins, and downstream effector kinases. Black arrows indicate recruitment, activation, or production; red arrows indicate negative regulation.

Research in the Haugh Laboratory has focused on signal transduction mediated by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors, growth hormone receptor, interleukin (IL)-2 and IL-4 receptors, CXCR chemokine receptors, and integrins. In terms of signaling pathways, a major effort in the lab has been devoted to studying signal transduction through phosphoinositide 3-kinases (PI3Ks), lipid kinases that are centrally involved in cell migration and chemotaxis, cell survival, and cell proliferation. As outlined in more detail below, we have studied the kinetics of PI3K action, its subcellular localization, and its crosstalk with other canonical signaling pathways. Other signaling proteins and pathways studied by the Haugh group include Ras and its activation of mitogen-activated protein kinase (MAPK) cascades, phospholipase C (PLC)/protein kinase C (PKC) signaling, protein-tyrosine phosphatases, Rho-family GTPases, JAK-STAT signaling, and mTOR regulation. In the context of cell migration, we are keenly interested in integrating signaling dynamics with those of adhesion and the actin cytoskeleton.