Nav: Home

Crystal-clear view of a key neuronal receptor opens door for new, targeted drugs

March 07, 2019

During brain development, billions of neuron nerve cells must find their accurate pathway in the brain in order to form trillions of neuronal circuits enabling us to enjoy cognitive, sensory and emotional wellbeing. To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons and their long extensions stay on the right path and avoid faulty turns. Rare defects in these neuronal guidance proteins can result in severe neurological conditions such as ataxia and epilepsy.

In a new study published in Cell, Bar-Ilan University researchers and collaborators report on their discovery of the intricate molecular mechanism that allows the guidance receptor "Robo" to react to signals in its environment, while avoiding premature activity that can lead to harmful outcomes.

One of the most important protein signaling systems that controls neuronal guidance consists of the cell surface receptor "Robo" and its cognate external guidance cue "Slit". The deficit of either of these proteins results in defects in brain structure and function. For example, their absence compromises the brain's ability to form the correct connection across the corpus callosum, which is the region where neuronal extensions from the two brain hemispheres cross paths to innervate opposite sides of the body, a fundamental attribute of bilateral creatures.

"Slit and Robo are highly conserved throughout evolution, and can be identified in virtually all animals with a nervous system, from a one-millimeter-long nematode all the way to humans, an aspect that highlights their importance," explains Prof. Yarden Opatowsky, Director of the Laboratory of Structural Biology in the Mina and Everard Goodman Faculty of Life Sciences at Bar-Ilan University, Israel. Using X-ray crystallography, Opatowsky, graduate student Reut Barak, and their colleagues and collaborators determined several atomic structures of Robo. "It took us six years to get the desired structure, but it was just the first phase of our research," says Opatowsky. The structures indicated very nicely how two Robo receptors form dimers and how their dimerization interfaces can be blocked." This led lab manager Dr. Julia Guez-Haddad and graduate student Galit Yom-Tov to embark on a series of biochemical and functional experiments to follow up on the structure-driven hypotheses.

A comprehensive model for Robo activation

Since their discovery about two decades ago, there has been a lot of progress towards understanding Slit-Robo function and the developmental responses that they trigger in the brain, as well as outside the central nervous system. However, scientists still have an incomplete understanding of how Slit activates Robo and what keeps Robo from getting activated in the absence of Slit. Following up on the new crystallographic observations, Opatowsky's team developed a new biochemical assay that allowed them to monitor Robo dimerization when expressed in cultured cells. In this way, they corroborated the structural model for Robo's self-control over its oligomeric state and also showed that the same mechanism actually exists in other closely related receptors. But does the new model hold true in an actual living biological system? Opatowsky explains: "Here we took a reductionist approach by examining the fate of one specific neuron type. In the course of evolution, Robo and Slit were duplicated several times, a process that resulted with humans and mice having four Robo genes and three Slits, where each copy has its own special attributes, but also maintains considerable redundant functions. We figured that conducting our experiments in creatures with such a high level of Robo and Slit redundancy may turn out to be like playing genetic 'whack-a-mole', where knocking out one Robo or Slit copy will be compensated by the upregulation of another copy. Luckily for us, the tiny C. elegans nematode has only one Robo and one Slit and was previously characterized for Slit and Robo function, which makes it ideal for our purposes. The evolutionary distance between humans and C. elegans is about 500 million years, and yet, all the experiments that we conducted point toward a similar Robo molecular mechanism."

Robo is an attractive drug target

When Robo and Slit are not expressed properly they are involved in the formation and progression of various developmental and chronic conditions, such as age-related macular degeneration, loss of bone mass, and kidney diseases. The involvement of Slit and Robo in cancer is of particular interest to researchers. Normally our cells rely on external signals for their growth, differentiation, migration, and eventual elimination. These external signals activate cellular receptors that relay the correct instructions into the cell. In cancer, some receptors are "hijacked" to drive tumor formation, progression and metastasis. In personalized cancer therapy based on the genetic profile of the patient's tumor, drugs are used to block these rogue receptors, thereby depriving cancer cells with vital signaling instructions and directing them toward destruction. "Slit and Robo are aberrantly expressed in cancer and targeting them is long considered a promising therapeutic approach for incurable subtypes of pancreatic, skin and breast cancer," says Opatowsky. "However, there are currently no Robo directed drugs, and we hypothesized that it is due to an insufficient structural and mechanistic understanding of Robo activation and signaling. Our discoveries provide, for the first time, the information necessary to design effective drugs targeting Robo receptors. In particular, the crystal structures revealed molecular sites on the surface of Robo that when targeted by designed drugs will allow us to manipulate Robo activation and inhibition in patients, thus providing new possibilities for treatment in the war on cancer."
-end-


Bar-Ilan University

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Setbacks
Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".