Background: Cell-Matrix-Cytoskeletal Signaling:
Cells have an innate ability to "sense" or respond to their environment. They do so through activation of surface receptors that set off internal signaling cascades resulting in changes in cellular behavior and architecture. The extracellular matrix is a critical part of the cellular environment, surrounding cells and organs and serving an instructive role during development. My laboratory is interested in investigating the role of essential signaling mediators of cell-matrix-cytoskeletal signaling, including: focal adhesion kinase (FAK), proline rich tyrosine kinase (Pyk2) and integrin linked kinase (ILK). Investigation into the upstream activation and downstream signaling of these key proteins will shed light on many of the fundamental cellular processes that they impact such as cellular migration, differentiation, and survival in a wide variety of cell types.
Relevance to Disease and Blinding Disorders:
Defects in cell-matrix signaling may lie at the heart of a number of diseases and degenerative conditions. My lab is particularly interested in how these signaling pathways regulate eye development and how perturbation of their signaling may lead to defects in visual system wiring, as well as a number of blinding disorders such as microphthalmia (small eyes), congenital and mature cataracts, and retinal dysplasia/degeneration.
Approach: Conditional Knockout Mouse Models and Cellular Imaging:
Our approach is to delete key proteins in the cell-matrix signaling pathway in the visual system of mice using conditional mouse knockout models. Here we can analyze the distinct role that cell-matrix signaling may play in directing neuronal process outgrowth and connectivity (in ganglion cells of the retina), glial cell function (Muller glial cells of the retina) and orchestrating epithelial polarity, migration and matrix organization (in organs such as the lens). Our goal is to unravel the molecular mechanisms that govern cellular responses to the extracellular matrix in distinct cell types in the eye during development, and learn how it might be possible to correct pathological defects in the future.
Available Research Projects:
. Developmental Eye Defects: We are currently defining the role that FAK, Pyk2 and ILK signaling plays in mouse eye development and disease.
. Live Extracellular Matrix Modeling/Cellular Interaction: We will use the mouse ocular lens to investigate the molecular mechanisms whereby cell-matrix adhesions model the basement membrane interface in a 3D, physiological context. Introduction of fluorescently tagged signaling constructs, biosensors and matrix molecules (upstream and downstream of FAK/Pyk2/ILK) into an intact cultured lens will allow us to examine these physiological pathways in detail with confocal microscopy.
. Neuronal Branching, Process Extension, Connectivity: We will identify how FAK/Pyk2/ILK-mediated signaling impacts the retinal projection, including: axonal extension, dendritic arborization and synapse formation. The role of upstream neuronal guidance cues (such as ephrin, semaphorin and netrin signaling) and downstream impact on the neuronal cytoskeleton will be examined. The role of FAK family deletion specifically in Muller glial cells will also be examined using mouse knockout models.
. Identification of In Vivo Signaling Pathways: An innovative aspect of our research program will be to combine two new powerful genetic approaches (ASKA and pFLEX) to control expression of a mutated version of focal adhesion kinase (FAK) with temporal and cell-type specificity in the mouse. This approach will be undertaken in collaboration with other UCSF laboratories. It will identify key signaling pathways that may represent potential therapeutic targets in diseases related to perturbed basement membranes or neuronal process extension. |
Beggs, H.E. (2006) Retinal Lamination and Integrity of the Lens Capsule Basement Membrane Require Focal Adhesion Kinase Signaling. ( Manuscript in Preparation ).
Shober, M., Raghavan, S., Nikolova, M., Polak, L., Pasolli, A., Beggs, H., Reichardt L.F. and Fuchs E. (2006) Defining roles for focal adhesion kinase in actin dynamics and focal adhesion turnover. (Submitted)
Sundberg LJ, Thompson R, Beggs HE, Reichardt LF, Mack CP, Taylor JP. (2006) Inactivation of Focal Adhesion Kinase promotes smooth muscle cell differentiation. (Submitted).
DiMichele LA, Doherty J, Rojas M, Beggs HE, Reichardt LF, Mack CP, Taylor JM (2006) FAK is required for pathological hypertrophic cardiac remodeling but not for maintaining physiological heart function. (Submitted)
Essayem S, Kovacic-Milivojevic B, Baumbusch C, McDonagh S, Dolganov G, Howerton K, Larocque N, Ramiriz A, Ramos DM, Fisher SJ, Jorcano JL, Beggs H, Reichardt, LF, Ilic, D (2006) Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK. Oncogene. 25:1081-9
Braren R, Hu H, Beggs HE, Reichardt LF, Wang R: Cre-Mediated Deletion of fak in the Circulatory System Disrupts Vascular Remodeling. (2006) J. Cell Biology 172: 151-162.
Tilghman, R.W., Slack-Davis, J.K., Sergina, N., Martin, K.H., Iwanicki, M., Hershey, D., Beggs, H.E, Reichardt, L. and Parsons, J.T. (2005) Focal Adhesion Kinase is required for the spatial organization of the leading edge in migrating cells. J. Cell Science. 118: 2613-23.
Liu G*, Beggs HE*, Park H.-T, Tang H, Xiong W.-C, Reichardt LF, Wu J, Rao Y: Role of the focal adhesion kinase in netrin-induced axon outgrowth. Nature Neuroscience, 2004: 7(11) 1222-1232. (* co-first author)
Rico B, Beggs HE, Schahin-Reed D, Kimes N, Schmidt A, Reichardt LF: Control of Axonal Branching and Synapse Formation by Focal Adhesion Kinase. Nature Neuroscience 2004: 7(10) 1059-1069.
Beggs HE, Schahin-Reed D, Zang K, Goebbels S, Nave KA, Gorski J, Jones KR, Sretavan D, Reichardt LF: FAK deficiency in Cells Contributing to the Basement Membrane Results in Cortical Abnormalities Resembling Congenital Muscular Dystrophies. Neuron, 2003: 40(3) 501-514.
Beggs HE, Baragona SC , Hemperly JJ, Maness PF: NCAM 140 interacts with the focal adhesion kinase p125FAK and the src -related tyrosine kinase p59 fyn. Journal of Biological Chemistry, 1997: 272(13) 8310-8319.
Maness PF, Beggs HE, Klinz SG, Morse WR: Selective neural cell adhesion molecule signaling by src family tyrosine kinases and phosphatases. Perspectives on Developmental Neurobiology, 1996: 4(2-3) 169-181.
Beggs HE, Soriano P, Marcus PF: NCAM-dependent neurite outgrowth is inhibited in neurons form fyn- minus mice. Journal of Cell Biology, 1994: 127:825-833 .
information last updated July 2006 |
Biomedical Sciences (BMS) Graduate Program
