Navigation Links
Molecular meet and greet
Date:8/18/2011

Boston, Mass. (Aug. 19, 2011)Researchers at Harvard Medical School have discovered that structural elements in the cell play a crucial role in organizing the motion of cell-surface receptors, proteins that enable cells to receive signals from other parts of the organism.

This discovery, published in the Aug. 19 issue of the journal Cell, fills a fundamental gap in the understanding of how cells relate to biochemical signals, including pharmaceuticals, and could have profound implications for drug development and the treatment of cancer and other diseases.

The findings are already prompting the design of a new lecture on cell signaling in one basic biochemistry course at HMS.

"We found that the way the receptors are organized in the membrane and the way they move around are controlled by the cytoskeleton," said Khuloud Jaqaman, instructor in the Department of Systems Biology at HMS and first author of the study. This dynamic organization promotes signaling function by encouraging receptors to cluster, even if briefly, she said.

Jaqaman and Gaudenz Danuser, HMS professor of cell biology, working with Sergio Grinstein from the Hospital for Sick Children in Toronto as well as colleagues at the University of Alberta, Edmonton, studied the motion of CD36, a receptor in human macrophages, a type of white blood cell that plays a role in immune response. CD36 detects oxidized LDL (oxLDL), a lipoprotein implicated in atherosclerosis.

Receptors are like the antennas in a cell's communication system with the world outside their membrane. The cytoskeleton, which includes a fine meshwork of actin fibers and an array of radiating microtubules, gives the cell its shape.

Like many receptors, CD36 can't work alone; a group of receptors must cluster together to send a signal into the cell. Until now, very little was known about how those functional groups of receptors formed. The cell and receptors were thought to wait "at rest" until a chemical signal happened to appear, causing receptors to coalesce.

This study reveals a much more dynamic "before" picture, with structures that precondition the cell to respond to signals. The researchers say that their work clearly demonstrates how "resting" receptor movements are functionally relevant to the transmission of signals into the cell.

Grinstein, a senior scientist at Toronto's Hospital for Sick Children whose interests include understanding how macrophages work, approached Danuser for imaging and analysis expertise. Grinstein wanted to study CD36 at the single-molecule level in live cells and in real time under a microscope.

Using an automated particle-tracking algorithm she had developed to overcome the challenges of imaging such minute, complex interactions, Jaqaman analyzed these single-molecule movies to dissect the receptor behavior and its regulation.

The movies reveal three kinds of motion by the receptors, which are sensitive to strands of the cytoskeleton's actin meshwork adjacent to the cell surface. As receptors roam about, they bump into these strands, slowing, stopping or changing direction. Some wander freely about the surface of the cell. Others become temporarily stuck inside a pocket of the mesh, as if trapped in a cage. Finally, some of the receptors travel linear paths.

These paths follow elongated "corridors" alongside the cell's microtubules, another part of the cell's cytoskeleton, radiating in more-or-less straight lines from the nucleus.

How the corridors form remains a mystery. The researchers suspect that they emerge from interactions between microtubules and actin, which remove actin strands from the path of the receptors.

In these narrow corridors free of actin strands, receptors scurry to and fro with more freedom, regularly bumping into one another, forming clusters that stick together fleetingly and then drift apart.

The researches suspected that these pre-formed clusters aid in signaling, so to test that theory, they disrupted the cytoskeleton. Sure enough, when the corridors disappeared, the cell no longer responded effectively to oxLDL.

Jaqaman compares the receptors in linear paths to people in the hallway of an office building. "People in the hallway are much more likely to bump into and chat with colleagues than people who stay in their offices all day, like receptors trapped in actin cages, or people wandering around the city, like receptors wandering freely around the cell surface," she says.

Jaqaman and Danuser stress that the mechanical nature of these structuresand how they relate to the cell's chemical and mechanical environmentmay be key to understanding how healthy and unhealthy cells function, replicate and grow. For example, it is well known, they said, that tumors are mechanically stiffer than normal tissues. In one provocative scenario, Danuser speculates that the broad variation in the mechanical properties between cancer tissues in different patients may be a key reason for the variable success of cancer chemotherapies that target cell-surface receptors.

"While most current research focuses on the study of oncogenes and tumor suppressors, it might be just the intrinsic change in cancer-tissue mechanics that leads to the change of signaling," Danuser said. "I think we absolutely have to look into that."


'/>"/>

Contact: David Cameron
david_cameron@hms.harvard.edu
617-432-0441
Harvard Medical School
Source:Eurekalert

Related medicine news :

1. Hebrew U. scientists identify molecular basis for DNA breakage
2. Blocking molecular target could make more cancers treatable with PARP inhibitors
3. Scientists discover new molecular pathway involved in wound-healing and temperature sensation
4. Molecular glue sticks it to cancer
5. Molecular movements could lead to new way to treat cancer
6. Scientists Find Molecular Similarities in Brains of Those With Autism
7. Autism changes molecular structure of the brain, UCLA study finds
8. Finding molecular targets of an HIV drug used in cancer therapy
9. Researchers publish molecular disease model for melanoma
10. Stanford researchers discover molecular determinant of cell identity
11. Using a molecular switch to turn on cancer vaccines
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/8/2016)... ... February 08, 2016 , ... ... states in the U.S. require dental technicians to be certified or obtain continuing ... industry, NADL created the “What’s In Your Mouth?” campaign to inform dentists and ...
(Date:2/7/2016)... ... February 07, 2016 , ... Women's Excellence staff, in all four locations, wore ... Wear Red Day is the first Friday each February and a day to bring ... in 3 deaths among women each year – more than all cancers combined. Go ...
(Date:2/7/2016)... ... 2016 , ... Dr. Todd Hobgood , certificated in ... surgical expertise. Technically known as deoxycholic acid or previously as ATX-101, Kybella® ... for reduction of fat below the chin (aka the “double chin”). Medication side ...
(Date:2/6/2016)... ... ... US Sports Camps is proud to sponsor the Bay Area Disc Association's ... leaders, ultimate organizations, and coaches from around the US. The theme for this year’s ... of Youth and Education, describes this year YUCC as “an important conversation we must ...
(Date:2/6/2016)... , ... February 06, 2016 , ... Shark Finds ... announce the launch of a new DRTV campaign with Belly Bands. , Having a ... everything from sprays to puppy pads and find nothing works, get Belly Bands, ...
Breaking Medicine News(10 mins):
(Date:2/8/2016)... Feb. 8, 2016   GS1 US will ... guide them through GS1 Standards implementation to address the ... Unique Device Identification (UDI) rule. Scott ... Beth Gibson , senior director industry development, medical devices, ... director, GS1 US --> Scott ...
(Date:2/8/2016)... Feb. 8, 2016 Nueterra, the ... specialized in the development of equity partnerships ... it has divided its interests between two ... Capital will continue the founding company,s private ... operate a national system of integrated provider ...
(Date:2/8/2016)... Pa. , Feb. 8, 2016   ... November Research Group (NRG),s pharmacovigilance technology services ... system-related consulting services and an Oracle Argus Specialized ... services to Life Sciences companies. ... and expands HighPoint,s life sciences capabilities and provides ...
Breaking Medicine Technology: