This is the first competitive renewal of grant for which the long term objective is to characterize the role of LAR in regulating cell-matrix interactions. LAR is a transmembrane, receptor-like protein tyrosine phosphatase (PTP), first isolated by the investigator, that displays features of an immunoglobulin superfamily cell adhesion molecule in its extracellular segment. In the course of the initial funding period, the investigator demonstrated several properties of LAR that were consistent with such a role. For example he demonstrated that; LAR is localized to regions of association between epithelial cells and basement membrane in diverse tissues; LAR and the intracellular, coiled-coil, LAR-interacting protein LIP.1 colocalize to focal adhesions; LAR binds a multidomain protein termed Trio which contains a rac-specific guanine nucleotide exchange factor (GEF) domain and a rho-specific GEF domain; and LAR-deficient fibroblasts derived from LAR-knockout mice have altered cell morphology. The investigator proposes to build on this foundation to test further the hypothesis that LAR regulates cell-matrix interactions by addressing the following specific aims. 1) To determine the role of the LAR binding protein LIP.1 in LAR-mediated signaling; 2) To determine the role of the LAR binding protein Trio in LAR-mediated signaling; 3) To identify the LAR substrate; and 4) To identify the extracellular ligand(s) of LAR. The investigator proposes to achieve these aims by: (i) characterizing cell lines overexpressing LIP.1 and characterizing LIP.1 binding proteins that may link LAR to other proteins including LAR substrates; ii) characterizing the LAR-Trio association in vivo, determining the effect of LAR expression on Trio transforming activity, and characterizing LAR-deficient cells and Trio-transformed cells; iii) identifying a protein that is hyper-tyrosine phosphorylated in LAR-deficient cells; and iv) purifying and characterizing LAR extracellular region-binding proteins, and determining the functional effect of LAR ligand binding.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055547-10
Application #
6341936
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Ault, Grace S
Project Start
1992-03-01
Project End
2001-09-30
Budget Start
2001-01-01
Budget End
2001-09-30
Support Year
10
Fiscal Year
2001
Total Cost
$323,382
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Serra-Pages, Carles; Streuli, Michel; Medley, Quintus G (2005) Liprin phosphorylation regulates binding to LAR: evidence for liprin autophosphorylation. Biochemistry 44:15715-24
Medley, Quintus G; Buchbinder, Elizabeth G; Tachibana, Kouichi et al. (2003) Signaling between focal adhesion kinase and trio. J Biol Chem 278:13265-70
Wyszynski, Michael; Kim, Eunjoon; Dunah, Anthone W et al. (2002) Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron 34:39-52
Seipel, K; O'Brien, S P; Iannotti, E et al. (2001) Tara, a novel F-actin binding protein, associates with the Trio guanine nucleotide exchange factor and regulates actin cytoskeletal organization. J Cell Sci 114:389-99
Medley, Q G; Serra-Pages, C; Iannotti, E et al. (2000) The trio guanine nucleotide exchange factor is a RhoA target. Binding of RhoA to the trio immunoglobulin-like domain. J Biol Chem 275:36116-23
Kickhoefer, V A; Siva, A C; Kedersha, N L et al. (1999) The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J Cell Biol 146:917-28
Seipel, K; Medley, Q G; Kedersha, N L et al. (1999) Trio amino-terminal guanine nucleotide exchange factor domain expression promotes actin cytoskeleton reorganization, cell migration and anchorage-independent cell growth. J Cell Sci 112 ( Pt 12):1825-34
Serra-Pages, C; Medley, Q G; Tang, M et al. (1998) Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem 273:15611-20
Taviaux, S; Diriong, S; Bellanger, J M et al. (1997) Assignment of TRIO, the Trio gene (PTPRF interacting) to human chromosome bands 5p 15.1-->p 14 by in situ hybridization. Cytogenet Cell Genet 76:107-8
Streuli, M (1996) Protein tyrosine phosphatases in signaling. Curr Opin Cell Biol 8:182-8

Showing the most recent 10 out of 16 publications