Research yields potential target for cancer, wound healing and fibrosis

Mar 18, 2009

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, β1 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 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 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 and excessive scarring. Therefore, understanding how cells regulate the ability of integrins to control the abundance of fibrillar fibronectin is of therapeutic interest.

These beta-1 tail mutations are thought to disrupt the ability of the beta-tail to interact with their recruited proteins. The team found a defect in assembling fibronectin fibrils for the majority of the beta-1 integrin tail mutations. Further studies focused on studying two cell lines that were both unable to form fibrils. When adhesion to fibronectin was examined, one cell line spread whereas the other did not. They demonstrated that specific beta-1 tail mutations can affect cell signaling, cell spreading or formation of fibronectin fibrils. These studies revealed an ability of the cell to sort out different ways of controlling various integrin activities. For instance, the integrin beta-1 tail specifically recruited a protein called talin, found in this study to be important for integrins to form fibronectin fibrils, yet talin was dispensable for early cell spreading events. This ability to selectively adjust particular functions of the integrin may be a key to preventing the progression of diseases associated with abnormal integrin signaling or fibronectin fibril formation such as in and fibrosis.

"Based upon these studies, the aim of my current research at the LSU Health Sciences Center New Orleans School of Dentistry focuses on those proteins that connect to integrin beta-tails in oral cancer because this knowledge will aid in developing therapeutics that selectively target aberrant integrin functions in oral cancer, " notes Dr. Berrier.

"Understanding the mechanisms by which the beta-1 integrin controls the many functions that it regulates is critical to designing drugs that are specific enough to block defective functions of the integrin while simultaneously maintaining normal activities of the integrin in healthy tissue," said Dr. Green.

Source: Louisiana State University Health Sciences Center

Explore further: Structure of sodium channels different than previously believed

add to favorites email to friend print save as pdf

Related Stories

Blocking beta1-integrin to treat cancer

Jun 06, 2007

Targeting the function of a protein known as beta1-integrin might represent a novel approach to cancer treatment, according to a paper published online in The EMBO Journal this week. Blocking the action of this protein could ...

Researchers discover new drug target for inflammatory disease

Sep 22, 2008

UC Davis researchers have defined a cellular process that promotes inflammation and, at the same time, found an important starting point for identifying and testing new drugs for diseases such as sepsis, rheumatoid arthritis, ...

Potential therapy for congenital muscular dystrophy

Dec 30, 2008

Current research suggests laminin, a protein that helps cells stick together, may lead to enhanced muscle repair in muscular dystrophy. The related report by Rooney et al, "Laminin-111 restores regenerative capacity in a ...

Scientists identify new cellular receptor for HIV

Feb 10, 2008

A cellular protein that helps guide immune cells to the gut has been newly identified as a target of HIV when the virus begins its assault on the body's immune system, according to researchers from the National Institute ...

Protein helps immune cells to divide and conquer

Mar 08, 2009

Researchers at the University of California, San Diego School of Medicine have identified a key protein that is required for immune cells called B lymphocytes to divide and replicate themselves. The rapid generation of large ...

Recommended for you

Breakthrough points to new drugs from nature

Apr 16, 2014

Researchers at Griffith University's Eskitis Institute have developed a new technique for discovering natural compounds which could form the basis of novel therapeutic drugs.

World's first successful visualisation of key coenzyme

Apr 16, 2014

Japanese researchers have successfully developed the world's first imaging method for visualising the behaviour of nicotine-adenine dinucleotide derivative (NAD(P)H), a key coenzyme, inside cells. This feat ...

User comments : 0

More news stories

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...