Nav: Home

First complete interactome map of human receptor tyrosine kinases and phosphatases

January 05, 2017

In 2011, Igor Stagljar, a professor in the University of Toronto's Donnelly Centre, came across a study that genetically linked two genes in the cell to a hard-to-treat (triple negative) breast cancer. It was not clear how the proteins encoded by these genes worked, but Stagljar had a unique way to find out.

One of the proteins, called epidermal growth factor receptor (EGFR), belonged to a group called receptor tyrosine kinases (RTK), which tell the cell to grow and divide in response to signals from the cell's environment. The other one (PTPN12) was from the protein tyrosine phosphatase (PTP) class, which mainly work by shutting the RTKs down. However, the EGFR is wedged within the cell's outer envelope, or membrane, making it difficult to study by traditional methods. But with the help of MYTH and MaMTH, technologies developed in Stagljar's lab, Dr. Zhong Yao, a senior research associate in the lab, was able to show that the two proteins came into direct contact with each other. This led further support to the thinking that some breast cancers progress when the link between this particular RTK and PTP is broken, unleashing unchecked RTK signalling and, consequently, cell proliferation.

But Yao did not stop there. The high-throughput power of MYTH and MaMTH allowed him to investigate interactions between almost all human RTKs and PTPs. The resulting map charts more than RTK-PTP 300 interactions, most of which were unknown. The study will be published in the journal Molecular Cell on January 5.

"We tested interactions between almost all 58 RTKs and 144 PTPs that exist in human cells. Our map reveals new and surprising ways in which these proteins work together. These insights will help us better understand what goes wrong in cancer in order to develop more effective treatments," said Stagljar, who is also a professor in U of T's Departments of Molecular Genetics and Biochemistry.

RTKs are often mutated and hyperactive in many cancers, but only a fifth of them have been studied in enough detail to be targeted by the new generation of anti-cancer drugs called Tyrosine Kinase Inhibitors (TKIs). Yet these are some of the most promising treatments available because TKIs specifically target a mutated form of the RTK protein that's gone rogue in cancer cells, but not the normal RTK form, thus having fewer side effects than the blanket chemotherapy approach.

Lodged inside the cell membrane, with parts sticking out on either side of the cell, the RTKs act as antennae to relay signals from the outside world. When a signal--a hormone for example--arrives, an RTK attaches a phosphate group on its tail just below the cell's surface, triggering a cascade of biochemical reactions that enable the cells to grow and multiply. RTK activation is tightly controlled by the PTPs, most of which are also tethered to the membrane, whose job is to remove the phosphate group and stop the signaling cascade.

Traditional methods fall short from capturing short-lived membrane protein interactions because the surrounding membrane has to be dissolved, which changes the proteins' behaviour. Stagljar bridged this gap by developing MYTH and MaMTH which measure such fleeting interactions between membrane proteins in their natural setting in yeast and mammalian cells, respectively.

The project was done in collaboration with two leading experts in PTP biology Professors Anne-Claude Gingras, of the Lunenfeld-Tanenbaum Research institute the U of T's Department of Molecular Genetics, and Benjamin Neel, formerly of the Princess Margaret Cancer Center, UHN, currently at the New York University.

The researchers were surprised to find that some PTPs defy convention and act to promote RTK signalling suggesting that their roles are more complex than previously thought. For example, a phosphatase called PTPRA activates the EGFR, which is mutated in many cancers, revealing a new way in which cancer might spread. They also found two new phosphatases, PTPRB and PTPRH, which work as expected by grinding EGFR signalling to a halt, with potential anti-tumour properties.

"We wanted to show that these two assays, MYTH and MaMTH, that we developed in our lab, are suitable for studying these two important classes of proteins on such a large scale resulting in wealth of important data that can be used to develop new therapies against various type of cancer," said Stagljar. "Ultimately we want to build a map of interactions with all 3,000 or so human membrane proteins, of which at least 500 have direct roles in the onset of many human diseases. This will keep us busy," he added.
-end-


University of Toronto

Related Cancer Articles:

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.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 3: Shared Immunity
More than a million people have caught Covid-19, and tens of thousands have died. But thousands more have survived and recovered. A week or so ago (aka, what feels like ten years in corona time) producer Molly Webster learned that many of those survivors possess a kind of superpower: antibodies trained to fight the virus. Not only that, they might be able to pass this power on to the people who are sick with corona, and still in the fight. Today we have the story of an experimental treatment that's popping up all over the country: convalescent plasma transfusion, a century-old procedure that some say may become one of our best weapons against this devastating, new disease.   If you have recovered from Covid-19 and want to donate plasma, national and local donation registries are gearing up to collect blood.  To sign up with the American Red Cross, a national organization that works in local communities, head here.  To find out more about the The National COVID-19 Convalescent Plasma Project, which we spoke about in our episode, including information on clinical trials or plasma donation projects in your community, go here.  And if you are in the greater New York City area, and want to donate convalescent plasma, head over to the New York Blood Center to sign up. Or, register with specific NYC hospitals here.   If you are sick with Covid-19, and are interested in participating in a clinical trial, or are looking for a plasma donor match, check in with your local hospital, university, or blood center for more; you can also find more information on trials at The National COVID-19 Convalescent Plasma Project. And lastly, Tatiana Prowell's tweet that tipped us off is here. This episode was reported by Molly Webster and produced by Pat Walters. Special thanks to Drs. Evan Bloch and Tim Byun, as well as the Albert Einstein College of Medicine.  Support Radiolab today at Radiolab.org/donate.