Navigation Links
UCSD researchers create roadmap to integrin activation

Calling it an important technical advance in the study of the complex receptors and pathways of the body's cellular system, researchers at the University of California, San Diego (UCSD) School of Medicine have reconstructed the signaling pathways that impact activation of a receptor that is critical to the control of bleeding and to the thrombosis that occurs in heart attacks and strokes.

Their work to take apart and re-build the signaling pathway that regulates activation of the body's most abundant platelet receptor, an integrin called glycoprotein (GP) IIb-IIIa, provides a powerful and flexible tool for studying therapeutic targets along the pathway that impacts the activation process. This activation leads to changes in the cells' surface receptors ?changes that enable platelets to bind to the wall of blood vessels and to one another.

"The road map of the activation pathway could lead to the development of new antithrombotic drugs or treatments for inflammatory diseases. In addition, the ability to engineer these activation pathways may contribute to efforts to develop artificial platelets or leukocytes that could be used in patients with suppressed bone marrow function, for example," said Mark H. Ginsberg, M.D., professor of Medicine at the UCSD School of Medicine. The study will be published on line in Current Biology on September 19.

Integrins are a large family of adhesion molecules that promote stable interactions between cells and their environment. The integrins also act as cellular sensor and signaling molecules, transferring information between the inside and outside of a cell at plasma membrane sites.

Platelets stop the body's bleeding by sticking to one another. When a patient experiences a heart attack or stroke, the platelets stick inappropriately, clumping together and blocking the blood vessel. A signal from inside the platelet to the outside tells the GPIIb-IIIa integrin on the cell's surface to get sticky.

Direct inhibitors of GPIIb-IIIa binding include antithrombotics such as eptifibatide (Integrelin), abciximab (Reopro), and tirofiban (Aggrestat), drugs that reduce thrombosis, or formation of blood clots, by binding to the receptors and completely blocking their function. However, long-term administration of similar drugs doesn't work, in part because of the risk of serious bleeding complications in chronic use.

In sharp contrast, drugs such as clopidogrel (Plavix) and aspirin are two examples of antithrombotics that work well in chronic administration and are widely used for this purpose.

"Drugs such as aspirin and clopidogrel work in large part by blocking the activation of GPIIb-IIIa. These drugs don't work directly on GPIIb-IIIa, but do block signaling pathways that indirectly contribute to GPIIb-IIIa activation. Thus, they achieve a chronic anti-thrombotic effect with acceptable risk of bleeding ," said Ginsberg. He and his colleagues asked themselves if there was another way to block the receptors, by working at the step of activation when the receptors change from non-sticky to sticky ?in other words, by blocking the ability of GPIIb-IIIa to activate.

"Up until now, scientists have had a limited understanding of the pathways leading to platelet integrin activation, though we have developed a long list of what might impact the activation process," said Ginsberg. When cultured cells were engineered to express GPIIb-IIIa, agents that usually activated the platelet integrin failed to do so. The UCSD researchers realized that there was something missing, something special about platelets that impacted the activation process.

In 2003, Ginsberg, and Sanford Shattil, M.D., UCSD professor of medicine and Chief of Hematology/Oncology, and colleagues published a paper in the journal Science about the discovery that talin ? a large cytoplasmic protein that binds to the inside of an integrin or family of integrins ?delive rs the critical activation signal. Talin is very important in the linkage between a cell's cytoskeleton and integrins, linkages that cells use to migrate, for example. They noticed that platelets a have much higher concentration of talin that most other cells in the body.

"Talin binding seems to be what throws the activation switch," Ginsberg said. "By adding controllable amounts of talin and the enzyme protein kinase C ?an enzyme that modifies other proteins ?we found we can get the cell to respond to certain agents that, in turn, activate platelet integrin GPIIb-IIIa."

Using a synthetic approach, the scientists engineered an integrin-activated pathway. By adding protein kinase C, talin or mutants to manipulate the system, they hope to define and map sites where known drugs work, and discover targets along the pathway for new drugs.

"If you think of these pathways as interstate highways on a map, this study now enables us to see other back roads that lead to the destination," said Ginsberg.

Talin is also critical for activation of related integrins, such as those on white blood cells. In these cells, activation of integrins is a critical step in the sticking and migration of white blood cells required for inflammation in diseases such as rheumatoid arthritis and inflammatory bowel disease.


Source:University of California - San Diego

Related biology news :

1. NYU researchers simulate molecular biological clock
2. Vital step in cellular migration described by UCSD medical researchers
3. ASU researchers finds novel chemistry at work to provide parrots vibrant red colors
4. UCSD researchers maintain stem cells without contaminated animal feeder layers
5. Why do insects stop breathing? To avoid damage from too much oxygen, say researchers
6. New protein discovered by Hebrew University researchers
7. First real-time view of developing neurons reveals surprises, say Stanford researchers
8. Agilent Technologies releases automated literature search tool for biology researchers
9. Self-assembled nano-sized probes allow Penn researchers to see tumors through flesh and skin
10. Yale researchers identify molecule for detecting parasitic infection in humans
11. US life expectancy about to decline, researchers say
Post Your Comments:

(Date:10/27/2015)... 2015 In the present market scenario, security ... various industry verticals such as banking, healthcare, defense, electronic ... demand for secure & simplified access control and growing ... hacking of bank accounts, misuse of users, , and ... PC,s, laptops, and smartphones are expected to provide potential ...
(Date:10/27/2015)... Calif. , Oct. 27, 2015 Synaptics Inc. ... solutions, today announced that Google has adopted the Synaptics ... touch controller solutions to power its newest flagship smartphones, ... by Huawei. --> ... like Google to provide strategic collaboration in the joint ...
(Date:10/26/2015)... LAS VEGAS , Oct. 26, 2015 ... an innovator in modern authentication and a founding member ... launch of its latest version of the Nok Nok™ ... to use standards-based authentication that supports existing and emerging ... Suite is ideal for organizations deploying customer-facing applications that ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... YORK , November 24, 2015 ... in a European healthcare ... which the companies will work closely together in identifying European ... unmet medical need. The collaboration is underpinned by a significant ... fund. This is the first investment by Bristol-Myers Squibb in ...
(Date:11/23/2015)... 24, 2015 Women with a certain type of ... a higher risk of lung cancer than men with similar ... at the annual meeting of the Radiological Society of ... --> --> Lung nodules are small masses ... or subsolid based on their appearance on CT. Solid nodules ...
(Date:11/23/2015)... Columbia, Md. (PRWEB) , ... November 23, 2015 ... ... R&D 100 award for the development of its Nexera UC Unified Chromatography system. ... the 100 most technically significant new products of the year in the analytical ...
(Date:11/23/2015)... and PISCATAWAY, New Jersey , ... Crystallographic Data Centre (CCDC) announces the launch ... Database (CSD) and the CSD-System, now complemented by ... CSD-Discovery to support the discovery of new molecules, ... CSD-Enterprise, the complete set of the CCDC,s applications ...
Breaking Biology Technology: