One Key To Platelet Integrin Receptor Found in Transmembrane Region

(Philadelphia, 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 function.

"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 proteins.

"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 Health.

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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 $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 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 $392 million awarded in the 2016 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 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 2016, Penn Medicine provided $393 million to benefit our community.

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