One Key To Platelet Integrin Receptor Found in Transmembrane
PA) - Integrin receptors allow cells to attach to other
cells and to connective tissue which is necessary to
form tissues, organs, or even people, for that matter.
Researchers at the University of Pennsylvania School
of Medicine have demonstrated that a key to activating
alphaIIbbeta3, the integrin that allows platelets to
form blood clots, can be found in the part of the molecule
embedded within a platelet's outer membrane.
The alphaIIbbeta3 integrin, also known
as the platelet fibrinogen receptor or GP IIb-IIIa,
has been the focus of an entire class of blood-thinning
drugs, called GPIIb-IIIa agonists. The Penn researchers
findings, published in this week's issue of Science,
have implications for drugs created to thin the blood
and, perhaps more broadly, offer an intriguing hint
as to how integrins on cells throughout the body may
"The part of the GPIIb-IIIa molecule that
is embedded in the fatty layers that constitute the
platelet's outer membrane can determine whether or not
the integrin is activated, thereby making the platelet
'sticky,'" said Joel S. Bennett, MD, Professor
in Penn's Division of Hematology/Oncology within the
Department of Medicine. "The transmembrane region, which
was generally assumed to be just an anchor for keeping
the integrin receptor in place, can be an activating
switch for the entire molecule."
Once activated, the two subunits of GPIIb-IIIa
that extend outside the cell can clasp the walls of
a damaged blood vessel or a passing fibrinogen molecule
- much like a bobby pin can close around strands of
hair - thereby forming a normal blood clot or a pathologic
thrombus. GPIIb-IIIa agonist drugs, such as ReoPro®,
Integrilin®, and Aggrastat®, work by preventing activated
GPIIb-IIIa from binding to other objects in the bloodstream.
Since it is a protein, GPIIb-IIIa is made
up of amino acids, strung along in a specific sequence
to give the protein its shape. Bennett and his colleagues
were able to determine which amino acids are responsible
for activating GPIIb-IIIa by substituting a 'wrong'
amino acid at spaces along the protein chain and expressing
the mutant protein in cells growing in culture. They
found that the transmembrane portion of one of the GPIIb-IIIa
subunits is responsible for responding to activation
signals and, in return, causing groups of the activated
integrin to cluster.
"Remarkably, these regions are evolutionarily
conserved - meaning the transmembrane region in GPIIb-IIIa
is the same in apes or rabbits or mice as they are in
humans," said Bennett. "That tells us that the sequences
of the transmembrane region of integrins are important
factors in how these proteins function."
Moreover, nearly every integrin has a
different transmembrane region made up of a unique amino
acid sequence. If the transmembrane regions of all integrins
work on a similar scheme, it would provide a new paradigm
for the function of integrins and other cell membrane
"Integrin receptors are more than just
a cellular form of Velcro - as integrins bind, they
can also generate signals that command a cell to act,
such as whether to divide or differentiate or to produce
an important protein such as a gene transcription factor,"
said Bennett. "It will be interesting, and even medically
important, to determine how these signals can be modulated."
Other scientists involved in the research
paper described here include Renhao Li, Neal Mitra,
Holly Gratkowski, Gaston Vilaire, Reustem Litvinov,
Chandrasekaran Nagasami, John Weisel, James D. Lear,
and William F. DeGrado from Penn. This research was
supported by funding from the National Institutes of
# # #
Editor's Note: Dr.
Bennett does not hold financial interest in the manufacturers
of ReoPro®, Integrilin®, or Aggrastat®.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.