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Cells in humans and other vertebrates, as well as invertebrates, have signaling pathways that play a vital role in embryo development, cell proliferation, and tissue structuring. Deregulation in any of these signaling pathways, called beta-catenin-dependent Wnt signaling pathway, can cause embryo malformation and diseases such as bad cancer and cervical cancer. of the uterus.
Researchers at the Center for Medicinal Chemistry (CQMED) have discovered a way to regulate this pathway. Created with the support of the São Paulo Research Foundation – FAPESP as part of its Research Partnership Program for Technological Innovation (PITE), the CQMED is a unit of the Brazilian Agency for Research and Industrial Innovation (EMBRAPII), specializing in biopharmaceuticals and pharmaceuticals. The Center for Molecular Biology and Genetic Engineering Campinas (CBMEG) and the Institute of Biology of the same university (IB-UNICAMP).
CQMED is a partner of the Structural Genomics Consortium (SGC) and is also supported by the program of the National Institutes of Science and Technology (INCT) of (FAPESP), the National Council for Scientific and Technological Development (CNPq) and the Brazilian Coordination for the Improvement of Educational Personnel (CAPES).
The study was a collaboration between UNICAMP's CMS laboratories, the University of North Carolina at Chapel Hill (USA), Oxford University. (United Kingdom), Goethe University Frankfurt (Germany) and other research institutes located in the United States. , United Kingdom and Japan. The results were published in the journal Cell reports.
"By using a chemical synthesis compound that we have developed in recent years, we have been able to deepen our understanding of the regulation of the beta-catenin-dependent Wnt signaling pathway," said Roberta Regina Ruela de Souza at Agência FAPESP. Lead author of the study, Souza is a postdoctoral researcher at SGC-UNICAMP and benefits from a FAPESP scholarship. The chemical compound used to study the functions of the Wnt signaling pathway was a selective inhibitor of AP2-badociated kinase 1 (AAK1) developed by SGC-UNICAMP researchers.
Previous research has suggested the involvement of AAK1 in endocytosis, a process by which cells internalize substances from their external environment, such as micronutrients and even some viruses and bacteria. Endocytosis is known to play a role in regulating the Wnt signaling pathway, whereas inhibition of AAK1 appears to reduce its frequency.
To validate these hypotheses and study the specific function of AAK1 in Wnt signaling, these researchers used the inhibitor as a chemical probe – a small molecule capable of selectively binding to and inhibiting function of a protein linked to the disease in a biological model.
The badysis of the experimental results showed that AAK1 inhibits beta-catenin-dependent Wnt signaling in cells derived from various tissue types by promoting endocytosis of the receptor-related protein 6. low density lipoproteins (LRP6).
A signaling cascade along this pathway begins when the Wnt protein binds to LRP6, which is thereby activated and triggers an intracellular signal sequence that governs cellular development, growth and proliferation processes. Wnt also activates AAK1 to shut down; this prevents Wtn from proliferating indefinitely and causing signaling pathway problems that may lead to cancer or other diseases.
The researchers found that AAK1 deactivated Wnt by activating the endocytosis of LRP6, thereby reducing its presence in the cellular plasma membrane, so that it was no longer available to bind to Wnt. "In this way, AAK1 turns off the channel and interrupts the entire signaling cascade," said Souza.
Conversely, the researchers found that Wnt signaling is activated by the genetic silencing of AAK1 or by pharmacological inhibition with the molecule they have developed, which stabilizes the level of beta-catenin in the cells.
"These discoveries open up the possibility of regulating the activity of this signaling pathway," Souza said. "The chemical compound that inhibits AAK1 can make the path more active, for example, by allowing LRP6 to remain in the cellular plasma membrane."
Drug precursor
The results of the study also confirmed that the AAK1 inhibitor developed by the researchers could indeed be used as a chemical probe and precursor of a drug that interferes in the dependent processes of endocytosis, such as the penetration of certain viruses into the host cell.
The researchers plan to collaborate with other groups to study inhibitor applications in the prevention of infections, such as dengue fever, yellow fever and zika, caused by arboviruses (mosquito-borne viruses). , ticks and other arthropods).
"We know that arboviruses can infect cells by endocytosis, so if we inhibit this pathway using the chemical probe we developed, it will be possible to block the entry of these viruses into the cells," Souza said.
In accordance with the open science model used by the SGC to catalyze drug discovery, the AAK1 inhibitor will be placed in the public domain so that researchers from universities, research institutes and pharmaceutical companies can take advantage of this in studies leading to drug development. based on the molecule.
"SGC operates at the beginning of the drug discovery chain and we produce chemical probes for human proteins that can be used as initial molecules for drug development by the pharmaceutical industry," said Souza.
Seven other authors of the article, besides Souza, are affiliated with CQMED and SGC-UNICAMP.
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