Catch and release: collagen-mediated control of PEDF availability

May 26, 2020

Osaka, Japan - Cells are like tiny self-contained machines that are constantly fine-tuned in response to both internal and external signals. Some of these signals are induced by extracellular ligands, specialized proteins that bind to specific receptors on the cell surface, stimulating signaling pathways and altering gene expression.

One such ligand, called pigment epithelium-derived factor, or PEDF for short, is involved in multiple biological functions. Depending on which of its many cellular receptors it binds to, and even the timing of the binding, PEDF can either promote cell survival or trigger cell death. But until recently, researchers had no idea how PEDF itself was regulated.

In a study published in scientific journal PNAS, a research team led by Osaka University finally explain how cells make sure PEDF is in the right place at the right time.

"Previous studies had shown that collagen binding is very important for the function of PEDF," explains lead author of the study Kazuki Kawahara. "Therefore, we investigated the influence of collagen binding on the function of PEDF by examining the crystal structure of PEDF in complex with collagen."

Collagen is one of the most abundant proteins in the web-like structure called the extra-cellular matrix that surrounds human cells. This tangle of proteins and carbohydrates not only helps hold cells together, but also allows them to communicate with one another. As cells mature, the collagen matrix undergoes remodeling, characterized by tighter binding between collagen fibrils.

"The crystal structure revealed that PEDF binds to a cryptic site on the surface of type I collagen, where it is sequestered away from the cellular receptors," says Kawahara.

However, the researchers also found that a lysine residue in the binding site is involved in the crosslinking of collagen chains during collagen remodeling.

"We showed that PEDF binds to newly synthesized collagen but is gradually displaced as crosslinking increases," says senior author Yuji Kobayashi. "In this way, collagen controls the spatiotemporal accessibility of PEDF, regulating its interaction with target cell surface receptors."

PEDF has known anti-tumor and anti-angiogenic activities. Interestingly, the researchers found that PEDF selectively destroys developing vessels by binding to the newly synthesized collagen that is abundant on endothelial cells, which may then allow interaction with cellular receptors. This activity likely helps maintain homeostasis during tissue remodeling.

The researchers hope that this new information on the spatiotemporal control of PEDF will help in the development of novel therapies for cancer and vascular disease, as well as in the design of therapeutic biomaterials that target angiogenesis.
-end-
The article, "Spatiotemporal regulation of PEDF signaling by type I collagen remodeling," was published in Proceedings of the National Academy of Sciences of the United States of America at DOI: https://doi.org/10.1073/pnas.2004034117.

About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and now has expanded to one of Japan's leading comprehensive universities. The University has now embarked on open research revolution from a position as Japan's most innovative university and among the most innovative institutions in the world according to Reuters 2015 Top 100 Innovative Universities and the Nature Index Innovation 2017. The university's ability to innovate from the stage of fundamental research through the creation of useful technology with economic impact stems from its broad disciplinary spectrum.

Website: https://resou.osaka-u.ac.jp/en/top

Osaka University

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.