A protein long thought to provide only mechanical
support for keeping cells and tissues from literally
falling apart turns out to have much wider utility. In a
pair of reports, the protein K17 has been found to also
influence wound healing and maintain the structural
integrity of hair follicles, according to Johns Hopkins
researchers.
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 bedsores arising from
long periods of immobility. Along with the pain and
scarring, bedsores significantly increase health care costs
in nursing homes and hospitals.
A separate report by the same Johns 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 Johns 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,"
said the study's senior author, Pierre A. Coulombe,
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 said.
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," Coulombe said. "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,
Coulombe said.
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, resulting 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, Coulombe said.
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," Coulombe said.
The Johns 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.
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