The researchers began by referencing a previous discovery of their own: certain types of signaling molecules are detected by specific receptors (PDGFRα) in what are known as primary cilia. These cilia are present as single units on nearly all cell types in the human body and they function as cellular antennae that detect and transmit extracellular cues to control embryonic development and maintain tissue and organ function in adults.
The research group has now demonstrated that the very same antennae also play a crucial role in the balancing of the output of PDGFRα signaling so that the signaling doesn't get out of control. Unconstrained, excessive signaling from these receptors increases the risk - of brain tumor and gastrointestinal cancer development.
"Our results demonstrate that, under normal conditions, primary cilia serve to inhibit processes that can lead to cancer. We have shown that specific cancer-inhibiting proteins of the Cbl-family mediate the targeting of PDGFRα to the cilia, and once located in these antennae, the Cbl proteins prevent excessive receptor activation. Further, we have demonstrated that stabilization and functionality of the Cbl proteins are regulated by an entirely new mechanism, which also is associated with the cilia, according to the senior author.
Authors show that intraflagellar transport protein 20 (IFT20) interacts with E3 ubiquitin ligases c-Cbl and Cbl-b and is required for Cbl-mediated ubiquitination and internalization of PDGFRα for feedback inhibition of receptor signaling. “Should this mechanism be disturbed, the Cbl proteins will undergo self-destruction, which in turn will lead to mislocalization of the receptors to the general cell surface from where the receptors are wildly over-activated, "says the author.
The result is dramatic because cell antennae will now play an entirely new role in both our understanding of tumor progression and in the development of improved diagnostic and treatment methods for patients affected by certain types of cancer. According to the research group, it is likely that other illnesses are also linked to Cbl-protein protection errors.
"Defects in Cbl proteins are also associated with leukemia and autoimmune diseases. Therefore, our hope is that this discovery will contribute to a better understanding of the mechanisms that lead to these other very complicated illnesses," concludes the author.