Reversible protein tyrosine phosphorylation plays an essential role in regulating cell proliferation. Many receptor-linked protein tyrosine kinases (PTKs), including the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors, induce cell proliferation following ligand binding. The dysregulation of these PTKs can result in uncontrolled cell proliferation characteristic of neoplastic transformation. Indeed, about a third of all known oncogenes are PTKs. Regulation of protein tyrosine phosphorylation, however, requires the concerted activities of both PTKs and protein tyrosine phosphatases (PTPase). Although PTKs have been well characterized, it is only recently that a family of protein tyrosine phosphatases (PTPases) has been identified. One of these PTPases, designated LAR, possesses an extracellular domain whose structure resembles a cell adhesion receptor. Intriguingly, this putative adhesion receptor domain can be shed from the cell surface under conditions of high density cell culture. Taken together, these results suggest that the PTPase activity of LAR might be regulated by cell-cell interactions, and that LAR may play a role in cell-cell contact inhibition. Furthermore, the possibility that LAR is a tumor suppressor gene is supported by the finding that LAR is expressed in the same cell types that give rise to lung, breast, skin and colon cancers. The overall aim of this proposal is to increase our understanding of the role protein tyrosine phosphatases play in regulating cell proliferation.
The Specific Aims are: i) To determine the functional significance of LAR structural maturation, ii) To identify the physiological substrate(s) dephosphorylated by the LAR PTPase, iii) To identify the extracellular ligand of LAR, and iv) To determine the role of LAR gene transcription in regulating LAR function. The health-relatedness of the project is to increase our understanding of how cells are signalled to proliferate or stop proliferating.
These aims will be accomplished by: i) defining by mutational analysis the amino acid sequences required for LAR processing and shedding; ii) determining what signals induce LAR shedding, and whether these signals alter PTPase activity; iii) establishing LAR-negative cell lines to determine the functional role of the LAR PTPase; iv) identifying LAR substrates using immunochemical techniques; v) using purified, soluble LAR as an affinity probes to isolate the LAR ligand; and vi) determining the structure and regulation of the LAR gene promoter.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055547-04
Application #
2096680
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1992-03-01
Project End
1996-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
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

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