Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Protein key to cell motility has implications for stopping cancer metastasis


"Cell movement is the basic recipe of life, and all cells have the capacity to move," says Roberto Dominguez, PhD, professor of Physiology at the Perelman School of Medicine, University of Pennsylvania.

Motility – albeit on a cellular spatial scale -- is necessary for wound healing, clotting, fetal development, nerve connections, and the immune response, among other functions. On the other hand, cell movement can be deleterious when cancer cells break away from tumors and migrate to set up shop in other tissues during cancer metastasis.

The States of IRSp53

This image shows the active, open state of IRSp53 (top) and inactive, closed (bottom) state of IRSp53. In the closed state, cells do not generate filopodia as shown in the right bottom image (green=IRSp53, red=cdc42, and blue=actin, the most abundant protein in the cytoskeleton). The arrow between the two states indicates that the synergistic binding of Cdc42, cytoskeleton proteins (called downstream effectors of IRSp53 and includes the tumor-promoting factor Eps8) and the inherent attraction for the cell membrane, bring IRSp53 to specific locations on the cell membrane in which to change the shape of the cell. Chief among this reshaping activity is generating filopodia, the long thin objects coming off the cell in the top right image (color scheme as right bottom image). Note the change in pattern of the green and red show that IRSp53 and cdc42 are working together and moving to many different locations around the cell.

Credit: Roberto Dominguez, Ph.D., David Kast, Ph.D., Perelman School of Medicine, University of Pennsylvania

The Dominguez team, with postdoctoral fellow David Kast, PhD, and colleagues, report online ahead of print in Nature Structural & Molecular Biology how a key cell-movement protein called IRSp53 is regulated in a resting and active state, and what this means for cancer-cell metastasis.

"We characterized how IRSp53 connects to the cell-motility machinery," says Kast. "It does this by starting the formation of cell filopodia - extensions that form when a cell needs to move."

"Cells move like an inchworm," explains Dominguez. "Filopodia are at the leading edge of moving cells." The trailing end of the cell follows the move forward through contraction of actin and myosin in the cytoskeleton, much like muscle contraction. A cell pushes out the leading edge of its membrane, and sticks it down on whatever it is moving across, namely other cells, and then moves the cell body along, unsticking the back end. This sets the cell up for its next move.

IRSp53 contains a region called a BAR domain that binds to and shapes cell membranes. Other parts of the protein connect it to the cytoskeleton (internal bits that give a cell structure and shape). Together, through the binding of cell membranes and other proteins IRSp53 regulates cell movement. The team found that in the resting state, human IRSp53 adopts a closed shape that prevents it from interacting with the membrane and the cytoskeleton. However, the binding of a signaling protein, called Cdc42, opens IRSp53, setting in motion the recruitment of a complex cellular machinery needed for motility.

One of the cytoskeleton components IRSp53 connects to is the tumor-promoting protein Eps8. IRSp53 is synergistically activated by the combined action of Cdc42 and binding of Eps8, which is upregulated in metastatic cancers.

Co-authors Tatyana Svitkina and Changsong Yang from the Penn Department of Biology, brought their expertise with living cells to the study. By introducing normal and mutant proteins into cells they could see how these proteins induced filopodia to form. The team found that mutations in critical regions of IRSp53 can either lead to enhanced or reduced filopodia formation and, as a consequence, cell motility. "This finding shows how all these different proteins converge on IRSp53 to execute precise cellular functions, and that when one factor is disrupted, other proteins are affected down the activity pathway," says Dominguez.

The team's next steps will be to screen libraries of small molecule inhibitors that interfere with the IRSp53-Eps8 interaction, to figure out how to stop unwanted cell movement before it gets too far.

Coauthors include Yadaiah Madasu and Malgorzata Boczkowska, also from Physiology, and Andrea Disanza and Giorgio Scita from the Institute of Molecular Oncology and the University of Milan School of Medicine in Italy.

The research was funded by the National Institutes of Health (R01 MH087950, T32 AR053461, GM095977) and the American Cancer Society (PF-13-033-01-DMC).

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 $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 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 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; 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 2013, Penn Medicine provided $814 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:

Further reports about: Medicine cytoskeleton filopodia implications metastasis motility proteins

More articles from Life Sciences:

nachricht Strong, steady forces at work during cell division
20.10.2016 | University of Massachusetts at Amherst

nachricht Disturbance wanted
20.10.2016 | Max Delbrück Center for Molecular Medicine in the Helmholtz Association

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Innovative technique for shaping light could solve bandwidth crunch

20.10.2016 | Physics and Astronomy

Finding the lightest superdeformed triaxial atomic nucleus

20.10.2016 | Physics and Astronomy

NASA's MAVEN mission observes ups and downs of water escape from Mars

20.10.2016 | Physics and Astronomy

More VideoLinks >>>