Research conducted by Allison Berrier, PhD, Assistant Professor of Oral and Craniofacial Biology at the LSU Health Sciences Center New Orleans School of Dentistry, and colleagues, provides insights that may help scientists design novel approaches to control wound healing and fight diseases such as cancer and fibrosis.
The paper, â1 Integrin Cytoplasmic Domain Residues Selectively Modulate Fibronectin Matrix Assembly and Cell Spreading through Talin and Akt-1, will be published in the March 20, 2009 issue of the Journal of Biological Chemistry . The research team also included Drs. J. Angelo Green and Kenneth Yamada at the National Institute of Dental and Craniofacial Research, as well as Dr. Roumen Pankov at Sofia University in Sofia, Bulgaria.
The research concerns the regulation of integrins – proteins on the surface of cells that serve dual roles of anchoring cells within tissues and controlling cell behavior. Integrins anchor to extracellular proteins found outside the cell and this contact regulates important cellular activities that are critical for survival, proliferation and differentiation in both healthy tissues and tumors. Integrins are involved in the cellular response to injury and infection and are needed to repair damaged tissue.
Of the many integrins that exist, the beta-1 integrin is of great interest because it is involved in nearly every cell in the body. Its importance is demonstrated by the fact that mice, which are typically used as models for disease, cannot survive without the beta-1 integrin gene.
Beta-1 integrin is a cell surface protein that spans the membrane and has a portion of the protein outside the cell and a portion of the protein inside the cell. The beta-1 integrin tail is the portion found inside the cell. The beta-1 integrin tail has two functions -- it connects integrins to the cellular infrastructure and to signaling pathways.
This study advances earlier research on the beta-1 integrin tail, that revealed the ability of this integrin tail to provide a scaffold for signaling proteins that control cell survival. The extracellular matrix is a complex mixture containing proteins such as fibronectin and collagen that provide structural support to cells and traction for cell movement. If cells are placed on top of extracellular matrix proteins the cells become activated by their integrins and trigger signaling for the cell to expand or spread over the matrix. Cell spreading is an intermediate step during cell migration on matrix proteins. Prior to the current study it was not clear whether the beta-1 integrin tail recruits the same or different proteins inside the cell to control two different integrin receptor functions outside the cell, namely, formation of fibronectin fibrils and cell spreading.
The researchers generated a panel of stable cell lines containing different mutations in cells of the beta-1 integrin tail. In the current study, the cell lines were used to determine the role of the beta-1 integrin tail in cell spreading and the production of fibronectin fibrils. Fibronectin is an anchorage protein present in connective tissues and it helps wound healing when it is deposited in damaged tissue. Cells can use their integrins to stretch fibronectin along their surface and this stretched or fibrillar fibronectin provides a docking site to bind additional fibronectin and other factors involved in inflammation and wound healing. An overabundance of fibrillar fibronectin around the cell is characteristic of fibrosis and excessive scarring. Therefore, understanding how cells regulate the ability of integrins to control the abundance of fibrillar fibronectin is of therapeutic interest.