Bedsores And Bald Hides: Novel Roles Revealed For A 'Scaffolding' Protein

The wound-healing work, published in the May 18 issue of Nature, sheds light on how the body repairs wounds and may have implications for preventing or treating chronic wounds such as pressure or bed sores arising from long periods of immobility. Along with the pain and scarring, bed sores significantly increase health care costs in nursing homes and hospitals.

A separate report by the same Hopkins group, published in the May 15 issue of Genes and Development, reports a new and different role for the same protein in promoting hair follicle growth, although the investigators were quick to caution that there's nothing in their work - yet - to suggest a way to prevent or cure human baldness.

K17 belongs to a family of proteins known as keratin intermediate filaments, which are part of the cytoskeleton, an intricate network of flexible protein fibers that maintain cell shape and strength. By studying mice genetically engineered to lack K17, the Hopkins researchers discovered that cells need it to turn on signals that lead to the manufacture of new proteins and cell growth when skin is damaged.

"Here we show an entirely novel and possibly independent, nonmechanical function in which these filaments latch onto and regulate cell signaling proteins," says the study's senior author, Pierre A. Coulombe, Ph.D., professor of biological chemistry in the Institute for Basic Biomedical Sciences at Hopkins. "The involvement of K17 in wound healing has not previously been known to influence the making of proteins, and this information has profound implications for our understanding of the role of the cytoskeleton in damaged cells," Coulombe says.

When the skin of normal mice is wounded, the skin cells surrounding the wound make more K17 protein and more proteins in general, and become much larger than intact skin cells. Mice lacking the K17 protein are slower at healing skin wounds than normal mice.

According to the researchers, mice without K17 are slower at making new proteins, and their skin cells stay smaller than skin cells with K17. Cell growth resulting from the manufacture of new proteins is in part controlled by several protein catalysts, or enzymes, including two called Akt and mTOR. The researchers found that cells lacking K17 also have a less active Akt/mTOR pathway, suggesting that K17 somehow interacts with Akt/mTOR to control cell growth and protein synthesis.

By treating cells with a chemical "super-glue" that causes proteins in the cells to stick to their nearest neighbors, the research team was able to fish out K17 and all other proteins stuck to it. One of these, called 14-3-3(sigma) not only binds to K17, but has been thought to activate the Akt/mTOR pathway to increase protein synthesis and cell size. In further experiments, the investigators reintroduced normal K17 protein into cells that lack it, which caused 14-3-3(sigma) to bind to K17, increased the rate of new protein manufacture by 30 percent and increased the size of the cells.

"What's clear from these experiments is that the presence of K17 in these skin cells contributes to turning on the molecular pathways that lead to protein synthesis and cell growth, and this promotes timely healing of skin wounds," says Coulombe. "The capacity for wound healing decreases with age, and a better understanding of the fundamental mechanisms involved in repairing wounds may lead to improved strategies for fostering proper healing with minimal scarring."

K17's role in maintaining hair follicle strength is probably centered on its capacity to control the timing of follicle cell death during normal hair growth cycles, says Coulombe.

The team previously reported that mice lacking the K17 protein fail to grow a healthy coat of body hair during the first week after birth. It turns out that without K17, cells in the hair follicle die too soon, which results in a thin coat of fragile hair, a condition resembling alopecia or thinning, balding hair. That the hair is fragile is not surprising given that K17 is a keratin protein, known to provide structure and strength, says Coulombe.

Hair follicle cells cycle continuously through three phases - growth, death and resting - during normal hair growth. According to the researchers, cells lacking K17 speed from growth to death faster than normal cells, preventing sufficient hair growth.

When cells of normal hair follicles die, they follow a specific and genetically controlled death program. The team found that the K17 cytoskeleton protein is required to physically interact with a protein that is known to activate cell death and prevent follicle cells from dying before they finish their growth phase.

"The cell death role of K17 is entirely independent of its structural support function and opens interesting doors to understanding hair and skin biology," says Coulombe.

The Hopkins researchers were funded chiefly by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, part of the National Institutes of Health.

Authors on the Nature paper are Seyun Kim, Pauline Wong and Coulombe. Authors on the Genes and Development paper are Xuemei Tong and Coulombe.