Receptor suppresses the immune response in order to save it

When viruses enter the body, they activate receptors on the surface of cells that allow viruses to invade those cells. A Yale-led team has found that one of the receptors, known as AXL, actually plays an essential role in the immune system’s ability to fight viral infections.

Prior studies have shown that the AXL receptor served as an immune “checkpoint,” limiting resistance to infection by suppressing immune cells. But those studies were only performed in tissue culture. To examine the role of AXL in animals, the research team tested the immune response to influenza A and West Nile viruses in mice. They found that mice lacking AXL were more susceptible to infection because their immune cells did not have enough information to marshal an adequate defense.

“In an organism, it turns out it’s good for some immune system cells to get infected—to ‘see’ the virus—so you can mount a good immune response,” said Carla Rothlin associate professor of immunobiology and pharmacology, and senior author on the study. The finding should inform the development of drugs designed to inhibit AXL for treatment of flu and West Nile, as well as cancer, she noted.

Edward T. Schmid, a former graduate student in Rothlin’s lab, was first author. The study was published June 28 in eLife.

Explore further: Scientists pinpoint pathway of resistance to viral infections in the gut

More information: Edward T Schmid et al. AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity, eLife (2016). DOI: 10.7554/eLife.12414

Journal reference: eLife search and more info website

Provided by: Yale University

From Wiki:

AXL gene

Tyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.[1][2] The gene was initially designated as UFO, in allusion to the unidentified function of this protein.[3]

Function

The protein encoded by this gene is a member of the receptor tyrosine kinase subfamily. Although it is similar to other receptor tyrosine kinases, the Axl protein represents a unique structure of the extracellular region that juxtaposes IgL and FNIII repeats. It transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation. This receptor can also mediate cell aggregation by homophilic binding. The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.[2]

Clinical significance

Axl is a chronic myelogenous leukemia-associated oncogene and also associated with colon cancer and melanoma. It is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.[2] There is ongoing research to develop possible drugs to target this signalling pathway and treat cancers.[4]

Interactions

AXL receptor tyrosine kinase has been shown to interact with TENC1.[5] Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival.

C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration.

We have previously identified C1 domain-containing phosphatase and TENsin homologue (C1-TEN) as being an intracellular binding partner for Axl receptor tyrosine kinase (RTK). C1-TEN is a tensin-related protein that houses an N-terminal region with predicted structural similarity to PTEN. Here, we report our observations on the effects of ectopic expression of C1-TEN in HEK293 cells, which resulted in profound molecular and phenotypic changes.

Stable expression of C1-TEN altered cellular morphology, with less cell spreading and weaker filamentous actin staining. Cells overexpressing C1-TEN were inhibited greatly in their proliferation and migration rates as compared with mock-transfected cells.

Furthermore, serum starvation-induced apoptosis caused a twofold increase in caspase 3 activity in C1-TEN-overexpressing cells vs. mock cells. In addition, C1-TEN-overexpressing cells showed a markedly reduced phosphorylation of Akt/PKB kinase and its substrate GSK3, as well as reduced Akt enzymatic activity. No such effects on JNK were observed.

Also, serum-stimulated activation of Akt was delayed in C1-TEN-overexpressing cells, while no difference in profile of ERK activation was observed.

Furthermore, cells expressing a C1-TEN mutant where the putative phosphatase active site cysteine at position 231 was substituted for a serine displayed full restoration of both cell proliferation and Akt activation. In conclusion, C1-TEN appears to be a novel intracellular phosphatase that negatively regulates the Akt/PKB signaling cascade, and is similar to its relative PTEN in this respect.

However, the particular domain organization of C1-TEN may enable it to regulate RTK and other signaling complexes that are linked to Akt/PKB signaling in a unique manner.

 

PMID: 15817639 DOI: 10.1096/fj.04-2532fje

Non-invasive method to kill cancer cells

Matthew Gdovin, an associate professor in the UTSA Department of Biology, has developed a newly patented method to kill cancer cells. His discovery, described in a new study in The Journal of Clinical Oncology, may tremendously help people with inoperable or hard-to-reach tumors, as well as young children stricken with cancer.

 

 

 

 

 

Gdovin’s top-tier research involves injecting a chemical compound, nitrobenzaldehyde, into the tumor and allowing it to diffuse into the tissue. He then aims a beam of light at the tissue, causing the cells to become very acidic inside and, essentially, commit suicide. Within two hours, Gdovin estimates up to 95 percent of the targeted cancer cells are dead.

 

“Even though there are many different types of cancers, the one thing they have in common is their susceptibility to this induced cell suicide,” he said.

Gdovin tested his method against triple negative breast cancer, one of the most aggressive types of cancer and one of the hardest to treat. The prognosis for triple negative breast cancer is usually very poor. After one treatment in the laboratory, he was able to stop the tumor from growing and double chances of survival in mice.

 

“All forms of cancer attempt to make cells acidic on the outside as a way to attract the attention of a blood vessel, which attempts to get rid of the acid,” he said. “Instead, the cancer latches onto the blood vessel and uses it to make the tumor larger and larger.”

 

Chemotherapy treatments target all cells in the body, and certain chemotherapeutics try to keep cancer cells acidic as a way to kill the cancer. This is what causes many cancer patients to lose their hair and become sickly. Gdovin’s method, however, is more precise and can target just the tumor.

 

In the past two years, he’s developed his photodynamic cancer therapy to the point where it’s non-invasive. It now requires just an injection of the nitrobenzaldehyde fluid followed by a flash of an ultraviolet light to cause the cancer-killing reaction. Gdovin has now begun to test the method on drug-resistant cancer cells to make his therapy as strong as possible. He’s also started to develop a nanoparticle that can be injected into the body to target metastasized cancer cells. The nanoparticle is activated with a wavelength of light that it can pass harmlessly through skin, flesh and bone and still activate the the cancer-killing nanoparticle.

 

Gdovin hopes that his non-invasive method will help cancer patients with tumors in areas that have proven problematic for surgeons, such as the brain stem, aorta or spine. It could also help people who have received the maximum amount of radiation treatment and can no longer cope with the scarring and pain that goes along with it, or children who are at risk of developing mutations from radiation as they grow older.

 

“There are so many types of cancer for which the prognosis is very poor,” he said. “We’re thinking outside the box and finding a way to do what for many people is simply impossible.”

 

Explore further: Mouse study: Triple-therapy cocktail shrinks triple-negative breast tumors

 

More information: Photodynamic acidification therapy to reduce triple negative breast cancer growth in vivo, meetinglibrary.asco.org/content/170361-176

 

Journal reference: Journal of Clinical Oncology search and more info website

 

Provided by: University of Texas at San Antonio search and more info