Integrative Cell Signaling
How does a cell know what to do and when to do it? This question forms the basis for the field of research called signal transduction. Here in the Department of Pharmacology at Yale, signal transduction is studied in a variety of different ways to understand how a cell transduces signals from the plasma membrane to the nucleus. Understanding this complex series of inter-connected cascades inside the cell will eventually provide a detailed roadmap for how cells work. The value that this information offers to the well-being of humans is immense. Signal transduction in Pharmacology provides the unique opportunity to uncover the basis of human disease and ultimately the development of novel therapeutic strategies to treat cancer, cardiovascular, neurological and metabolic disorders.
The strength of signal transduction research in the Department of Pharmacology is built upon an integrated platform from which faculty from different disciplines collaborate and bring to bear their expertise to solve a variety of distinct problems in the area of cell signaling. These research interests include the regulation of signal transduction by protein phosphorylation through the actions of protein kinases and protein phosphatases. Other areas of interest focus on the actions of G-protein-coupled receptors, phospholipids, calcium and gases as intracellular transducers. In many instances the inter-connectivity of these intracellular signaling pathways provides a portal to the outside world. How cells sense their environment through adhesion molecules and membrane channels are also areas of signal transduction research conducted in this department.
The study of signal transduction in Pharmacology at Yale is particularly exciting because of the potential impact that uncovering how these complex networks work might have on human disease. To accomplish these goals a variety of state-of-the-art techniques are applied and novel approaches to the study of signaling molecules are developed here in this department. In addition, researchers utilize mouse genetics approaches alongside the traditional tools of biochemistry and molecular biology to connect these signaling pathways to the broader goal of defining whether disruption of these pathways participates in the pathogenesis of human disease.
Signal Transduction Image Gallery
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- The Wnt signaling pathway. Image from the Wu Lab.
- Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006;21(5):711-7.
- From: Common and distinct elements in cellular signaling via EGF and FGF receptors. Schlessinger J. Science. 2004;306(5701):1506-7.
- Bidirectional signaling through integrin adhesion receptors involves the assembly and dynamic re-organization of multi-protein complexes that regulate integrin binding to extracellular ligands and transmit signals from integrins to intracellular signaling cascades. Image from the Calderwood lab.
- The figure shows peptide array analysis of phosphorylation specificity of twelve protein kinases from the budding yeast S. cerevisiae, each represented in a different color. Each row corresponds to an amino acid residue found at a specific position within a short peptide indicated by the column. Image from the Turk lab.
- Angiogenesis in the mouse ear is imaged with staining for the endothelial marker PECAM-1. Image from the Sessa Lab.
Extracellular domain structures of Receptor Tyrosine Kinases. (Front) The ternary complex structure of Fibroblast Growth Factor Receptor 1 (FGFR1) extracellular domain in complex with FGF2 and heparin. Two FGF2 molecules are colored in green, and two D2-D3 domains of FGFR1 in magenta and yellow. The heparin molecules are depicted in stick. (Back) The extracellular domain structure of KIT dimer in complex with Stem Cell Factor dimer (SCF).
SCF dimer mediates the complex formation of KIT extracellular domains. Five Ig-like domains of KIT extracellular domains are colored in blue, green, yellow, orange, and pale pink from D1 to D5, respectively. SCF dimer is colored in magenta. Image from the Schlessinger lab.
Activated Fibroblast Growth Factor Receptor 1 (FGFR1) in complex with tandem SH2 domains of Phospholipase Cγ (PLCγ). From far to near, the picture shows progression of the complex formation between FGFR1 and PLCγ. The kinase domain of FGFR1 in colored in green, N-terminal SH2 domain of PLCγ in cyan, and C-terminal SH2 domain in dark blue. An ATP and the substrate peptide are shown in stick, and a magnesium ion (Mg) in blue sphere.
The canonical phosphorylation-dependant primary binding site colored in blue is found between FGFR1 and PLCγ. In addition, the novel phosphorylation-independent secondary binding site colored in red is found in the complex structure. Image from the Schlessinger lab.
- Caveolin in atherosclerosis. From the Sessa Lab.
- A cross section of an atherosclerotic blood vessel stained for caveolin-1 (green), macrophages (red, F4/80) and DAPI (blue nuclear stain). Image from the Sessa Lab.
- MAP kinase phosphatase-1 controls infiltration of inflammatory cells in to diseased skeletal muscle. Left panel wild type muscle showing damaged area (red) and invading neutrophils (green). Right panel muscle from MAP kinase phosphatase-1 knock-outs showing increased neutrophil invasion. Shi et al, 2010, FASEB J., 24: 2985-2997
- Localization of F-actin (red) and the focal adhesion adaptor protein vinculin (green) in an endothelial cell spreading on the integrin ligand fibronectin. Note how the actin stress fibers span the cell and terminate in focal adhesions. Image from the Calderwood lab.
- MAP kinase phosphatases regulate muscle stem cell function to control muscle regeneration. Upper panels show wild type regenerating muscle. Lower panels MAP kinase phosphatase-1 knock-out mice, showing disrupted muscle regeneration in response to injury. Shi et al, 2010, FASEB J., 24: 2985-2997