Protein may be target for new cancer drugs

January 24, 2002

During development of multicellular organisms, cells are bombarded by signals from their environment. The repertoire of receptors that cells display on their surfaces often determines whether or not individual cells respond to environmental cues.

Researchers have now found that a protein that oversees the transport of receptors from the surface to the interior of the cell also tags receptors for degradation. This finding is important because cells turn off their response to external growth signals by decreasing the number of receptors available to bind signals.

In an article published in the January 25, 2002, issue of Cell, Howard Hughes Medical Institute investigator Hugo J. Bellen and colleagues at Baylor College of Medicine report that the activity of the protein Hrs may regulate cell proliferation and could be an important new target for anticancer drugs.

A process called endocytosis regulates the cell-surface expression of many receptors. During endocytosis, a patch of the cell membrane containing the receptor is internalized by the cell and forms small vesicles that later fuse into a large vesicle called the endosome. From the endosome, growth factor receptors and other cargo may be recycled back to the cell surface, or they may sent to another compartment, called the lysosome, where they can be degraded.

According to Bellen, experiments in yeast by other researchers -- including HHMI investigator Scott D. Emr at the University of California, San Diego -- suggested that Hrs might be involved in endocytosis, but its specific function remained unknown. Bellen's group analyzed mutant fly larvae that lacked functional Hrs in order to try to understand the protein's role in endocytosis during development.

Using electron microscopy, the researchers revealed how specific cells in the flies' stomachs absorbed a fluid tracer. The studies showed that the mutant flies had enlarged endosomes. They found that the abnormalities were due to defects in the endosome's ability to form "multi-vesicular bodies," specialized endosomes that contain vesicles inside them that carry cargo to the lysosome.

"What's exciting in this finding is that we now understand one reason why multi-vesicular bodies form," said Bellen. "Our later studies showed that these bodies are needed to turn off signals from key receptors involved in cellular communication."

The scientists demonstrated that epidermal growth factor receptor (EGFR) and Torso tyrosine kinase receptor remained switched on constantly in the mutant flies, because they depend on Hrs for inactivation. When they analyzed the Hrs protein, the scientists determined that it could bind specifically to a chemical tag that targets receptors to the lysosome for degradation.

A receptor may receive an external chemical signal such as a growth hormone at the cell surface, but that may not necessarily activate the cell's growth machinery, Bellen explained. "The signaling may not occur from most receptors at the cell membrane," Bellen noted. "For example, signaling may occur in the cytoplasm after the receptor has been taken in by endocytosis. When Hrs attaches to the receptor and pushes it inside the vesicle, this process would end its access to the cytoplasm and thus its signaling."

Receptors such as EGFR control cell proliferation, so their over-activity (caused by an absence of Hrs to guide them to the lysosome for degradation) might underlie many cancers, said Bellen. In fact, a protein called TSG101 that is missing in some forms of cancer has also been shown to play a role in forming multi-vesicular bodies.

"We know that Hrs is involved in regulating key signaling proteins that have been implicated in numerous cancers because they control cell proliferation and cell differentiation," he said. "Hrs should be studied in detail, not only to determine whether there are mutations in the protein that cause cancer, but also as a drug target. One could potentially use drugs to affect this protein's activity -- either to eliminate it or overexpress it -- to modify a signaling pathway."
-end-


Howard Hughes Medical Institute

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.