Fibronectin is a large protein (Mr about 250,000 daltons) that mediates the interaction of cells with the extracellular matrix. The molecule exists as a disulfide linked dimer that is elongated and flexible and participates in a complex set of macromolecular interactions in tissue that influence cell adhesion and migration. This well-studied matrix protein consists of multiple repeating modules of approximately 40-90 amino acids that can be classified into three types of homology units: types I, II and III. Clusters of these modules constitute individual fully active domains of the multifunctional molecule. Protein crystallography will be used to study the molecular basis for two biological roles of fibronectin: cell adhesion and matrix assembly. Type III modules are structural building blocks in the domains that mediate these two processes. Module III/10 contains an arginine-glycine-aspartic acid (RGD) sequence recognized by the alpha5beta1 cell surface adhesion receptor (integrin). Module III/1 binds to the type I modules at the amino- and carboxyl regions of fibronectin in a self-association mode prior to the formation of extracellular matrix. A fragment of module III/1 (III/1-C) binds to fibronectin (module III/11) and enhances fibronectin adhesiveness. The normal process of matrix assembly is disrupted in tumorigenic cells, and the lack of a stable accumulated matrix may influence the invasive properties of cancer cells. Recombinant fragments of fibronectin (i.e., including III/10, III/1, III/1-C and III/11 modules) as well as multimodule fragments (i.e., III/10-11, III/8- 10, III/8-11) will be crystallized. Also, module IIICS that exists in alternatively spliced variants of human fibronectin and is recognized by the alpha4beta1 integrin will be studied. Atomic models derived from these crystallographic analyses will be used to understand cell attachment and matrix assembly defects that permit tumor invasion and metastasis and to begin to construct a supra-structural image of fibronectin considering interactions of adjacent as well as distant modules.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA028896-16
Application #
6236593
Study Section
Project Start
1997-04-01
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
16
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
McLean, G W; Brown, K; Arbuckle, M I et al. (2001) Decreased focal adhesion kinase suppresses papilloma formation during experimental mouse skin carcinogenesis. Cancer Res 61:8385-9
Assa-Munt, N; Jia, X; Laakkonen, P et al. (2001) Solution structures and integrin binding activities of an RGD peptide with two isomers. Biochemistry 40:2373-8
Baneres, J L; Roquet, F; Martin, A et al. (2000) A minimized human integrin alpha(5)beta(1) that retains ligand recognition. J Biol Chem 275:5888-903
Ellerby, H M; Arap, W; Ellerby, L M et al. (1999) Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5:1032-8
Wang, B; Yang, H; Liu, Y C et al. (1999) Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display. Biochemistry 38:12499-504
Miura, R; Aspberg, A; Ethell, I M et al. (1999) The proteoglycan lectin domain binds sulfated cell surface glycolipids and promotes cell adhesion. J Biol Chem 274:11431-8
Ruoslahti, E (1999) Fibronectin and its integrin receptors in cancer. Adv Cancer Res 76:1-20
Orend, G; Hunter, T; Ruoslahti, E (1998) Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells. Oncogene 16:2575-83
Kodandapani, R; Veerapandian, L; Ni, C Z et al. (1998) Conformational change in an anti-integrin antibody: structure of OPG2 Fab bound to a beta 3 peptide. Biochem Biophys Res Commun 251:61-6
Arap, W; Pasqualini, R; Ruoslahti, E (1998) Chemotherapy targeted to tumor vasculature. Curr Opin Oncol 10:560-5

Showing the most recent 10 out of 129 publications