Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Cell BiologyRole of Cell Protrusionsin Cell Migration MechanismsTHE ADAMSLABORATORYPOSTDOCTORAL FELLOWRitu Chakravarti, Ph.D.RESEARCH TECHNICIANRaymond MonkGRADUATE STUDENTSoren PragSTUDENTJamie CannonThe research interest of my lab is in theresponses of cells to extracellular matrix.ECM is fundamental to cell interactions intissue organization and, by the formation ofadhesive contacts with cells, regulates cellfunction through effects on the cytoskeleton, oncell signaling processes and on gene expression.Matrix adhesion is thus crucial to normal cellinteractions. Changes in the expression orfunction of adhesion molecules have causal rolesin numerous genetic and acquired human diseases.We have focused on the responses to cellsto thrombospondin-1 (TSP-1), an ECM componentthat is highly associated with tissueremodeling and is also an inhibitor of angiogenesis.Cell adhesion to TSP1 induces cells to formprotrusive matrix-contacts based on fascin spikes.We have established molecular mechanisms thatare needed for assembly of fascin protrusions. Weare now investigating the role of fascin protrusionsin cell migration and invasion and thesignaling mechanisms by which fascin protrusionsare integrated with contractile focal adhesions.We are also defining the role of a novel intracellularprotein, muskelin, that affects cell spreadingon TSP1. Muskelin is a member of the kelchrepeat superfamily of proteins, many of whichact as components of large protein complexes.Understanding these cellular processes shouldidentify new candidate targets for translationalapplications.COLLABORATORSMartha K. Cathcart, Ph.D. 1Melissa L. Knothe Tate, Ph.D. 2Tony Ng, Ph.D. 3Marc S. Penn, M.D., Ph.D. 1Martin A. Schwartz, Ph.D. 41Dept .of Cell Biology, CCF2Dept. of BiomedicalEngineering, CCF3Cancer-Research UK, London4Univ. of Virginia,CharlottesvilleJosephine Adams, Ph.D.Adams, J.C., Kureishy, N., and A.L. Taylor (2001) A role for syndecan-1 in coupling fascin spike formationby thrombospondin-1. J. Cell Biol. 152:1169-1182.Anilkumar, N., Annis, D., Mosher, D.F., and J.C. Adams (2002) The trimeric assembly of thrombospondin-1or thrombospondi-2 is necessary for cell spreading and fascin spike organisation. J. Cell Sci. 115:2357-2366.Kureishy, N., Sapountzi, V., Prag, S., Anilkumar, N., and J.C. Adams (2002) Fascins, and their roles in cellstructure and function. Bioessays 24:350-361.Adams, J.C. (2002) Characterisation of a Drosophila melanogaster orthologue of muskelin. GENE 297:69-78.Jawhari, A.U., Buda, A., Jenkins, M., Shehzad, K., Sarraf, M., Noda, M., Farthing, M.J.G., Pignatelli, M. andAdams, J.C. (2003) Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness anddifferentiation in vitro. Am. J. Path. 162:69-80.Adams, J.C., Monk, R., Taylor, A., Ozbek, S., Fascetti, N., Baumgartner, S. and Engel, J. (2003)Characterisation of Drosophila thrombospondin defines an early origin of pentameric thrombospondins. J.Mol. Biol. 325: 479-494.68