The main objective of the proposed research plan is to investigate the mechanisms by which cell control their interactions with extracellular matrix and basement membranes during migration and differentiation in the normal and disease state. The integrin receptor heterodimer alpha1-beta1, a laminin/collagen receptor, has been chosen as a model system for this study because of several unique features. This molecular has a limited distribution in vivo, being present on activated lymphocytes, neuronal cells and in the mesangium of the kidney in adult tissues studied to date. This distribution implies a selective and specific function which is not fulfilled by other integrin collagen/laminin receptors (i.e., alpha2,3,and 6). This integrin can be induced on the surface of lymphocytes after activation in vitro, on PC12 cells in vitro, and in vivo on the synovial lymphocytes of patients with rheumatoid arthritis. Thus, this molecule probably is tightly regulated in vivo, and enables us to study the control of integrin function. cDNA clones for the human integrin alpha1 subunit will be used to produce fusion proteins and synthetic peptides for the generation of antibodies. The role of alpha1 in providing positional information in cell migrations crucial to normal development will be investigated by determining the temporal and spatial pattern of expression in mammalian embryos suing these probes. In particular, the presence of this integrin on migrating cells will allow us to determine if there are changes in expression levels from early in development, when the cells are migrating, to late, when they have reached their destination. Lastly, this integrin has shown different ligand specificities on varying cell types, binding laminin and collagen on some, while binding only collagen on others, a property which permits investigation of the factors both intrinsic and extrinsic to alpha1 which affect ligand specificity in cell migrations in vivo. These factors will be studied using intact, truncated and mutant forms of the molecule, the latter two generated by site-directed mutagenesis and heterologous eukaryotic expression systems. This research will enhance our knowledge of the mechanism of cell migration in both normal states such as development, and abnormal states such as tumor cell metastasis, and chronic inflammatory diseases; with the long term goal of determining the role of alpha1 and other integrins in the targeting of cells in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM044585-01
Application #
3303762
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Palazzo, Alexander F; Eng, Christina H; Schlaepfer, David D et al. (2004) Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science 303:836-9
Niu, Shi; Xie, Haichun; Marcantonio, Eugene E (2003) Integrin-mediated tyrosine phosphorylation of Shc in T cells is regulated by protein kinase C-dependent phosphorylations of Lck. Mol Biol Cell 14:349-60
Smilenov, L B; Mikhailov, A; Pelham, R J et al. (1999) Focal adhesion motility revealed in stationary fibroblasts. Science 286:1172-4
David, F S; Zage, P E; Marcantonio, E E (1999) Integrins interact with focal adhesions through multiple distinct pathways. J Cell Physiol 181:74-82
Zage, P E; Marcantonio, E E (1998) The membrane proximal region of the integrin beta cytoplasmic domain can mediate oligomerization. Cell Adhes Commun 5:335-47
Kern, A; Marcantonio, E E (1998) Role of the I-domain in collagen binding specificity and activation of the integrins alpha1beta1 and alpha2beta1. J Cell Physiol 176:634-41
Marcantonio, E E; David, F S (1997) Integrin receptor signaling: the propagation of an alpha-helix model. Matrix Biol 16:179-84
Wary, K K; Mainiero, F; Isakoff, S J et al. (1996) The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87:733-43
Hendey, B; Lawson, M; Marcantonio, E E et al. (1996) Intracellular calcium and calcineurin regulate neutrophil motility on vitronectin through a receptor identified by antibodies to integrins alphav and beta3. Blood 87:2038-48
Briesewitz, R; Kern, A; Smilenov, L B et al. (1996) The membrane-cytoplasm interface of integrin alpha subunits is critical for receptor latency. Mol Biol Cell 7:1499-509

Showing the most recent 10 out of 16 publications