Cells communicate with their environment through receptors on their surface. When a protein approaches these receptors, they can transmit a message inside the cell, for example the instruction to grow which can lead to the formation of tumors. New research by prof. Savvas Savvides (VIB-UGent, Belgium), the National Cancer Research Institute (Tokyo, Japan), the Memorial Sloan Kettering Cancer Center (New York, USA) and ℏ bioconsulting (Minnesota, USA) reveal the 3D structure of the ALK receptor, which is involved in various cancers and other diseases. This knowledge can lead to understanding the function of these receptors, an important first step towards therapeutic approaches. The work appears in the prestigious review Nature.
Message from the outside
Cells communicate with their environment through proteins that attach to receptors on the cell surface. Think of these receivers as communication antennas that can only receive specifically coded signals. When an appropriate signal from outside the cell – in the form of a specific protein for the receptor – approaches the antenna, the signal will be communicated inside the cell. It can initiate many important cellular processes, such as cell growth and division.
When the communication between these proteins and these receptors becomes uncontrolled, excessive or interrupted, it can lead to serious diseases such as cancer, inflammatory or autoimmune disorders. A group of receptors essential for human health are known as receptor tyrosine kinases (RTKs). We have about 58 of these RTKs organized into 20 families. The functional defects of these receptors are relevant for several cancers, autoimmune diseases, neurological and metabolic disorders.
Due to their critical roles in physiology and disease, most RTKs have been the subject of extensive research, but for one group, the ALK family, information is sorely lacking. We’ve known them for over three decades, and yet structural information about how they interact with their signaling proteins has remained a question mark.
This new study, led by doctoral student Steven De Munck from the team of prof. Savvas Savvides (VIB-UGent Center for Inflammation Research) has now revealed the 3D structure of ALK and LTK, another RTK, as well as their structures when linked to their activator proteins. This is essential information for understanding the function of these receptors.
We were surprised to see how unique and unprecedented these proteins and their assemblies are, illustrating how fundamental research is essential to discovering new concepts and mechanisms in pathogenic processes. “
Steven De Munck, doctoral student
ALK and its mutated versions are implicated, for example, in pediatric neuroblastoma, colon cancer, melanoma and possibly obesity as well. However, the lack of structural knowledge has prevented specific therapeutic targeting of ALK receptors.
Professor Savvides highlights the impact of their findings: “Front-line structural biology research is vital to solving difficult problems in biology, no matter how difficult such research may seem. It takes a talented and dedicated team of scientists like Steven to make breakthroughs. like this one, which will inspire innovative therapeutic approaches and open up new biomedical questions. “
De Munck, S., et al. (2021) Structural basis of cytokine-mediated activation of ALK family receptors. Nature. doi.org/10.1038/s41586-021-03959-5.