The enzyme PI3K has long been known for its important role in cell migration. However, new research has revealed that one of its subunits has the ability to put a stop to this process. In a recent study published in the journal Nature Communications, a team of scientists expanded our understanding of this crucial enzyme. They found that while PI3K functions as an accelerator to promote cell motility, it also has a built-in brake mechanism that hinders migration.I3K is a significant signaling enzyme that has been thoroughly researched for more than three decades due to its involvement in essential cellular activities such as growth, survival, movement, and metabolism,” explains Hideaki Matsubayashi, the study’s lead author and an assistant professor at Tohoku University’s Frontier Research Institute for Interdisciplinary Sciences (FRIS). “It plays a crucial role in cell migration and invasion, which, when not properly regulated, can lead to various pathologies. Our study found that PI3K can also actively inhibit these same migratory processes through a distinct non-catalytic endocytic mechanism originating from its p85β subunit.
Through the use of bioinformatics, molecular modeling, biochemical binding assays, and live-cell imaging, Matsubayashi and his team showed that a disordered region in p85β’s inter-SH2 domain binds directly to the endocytic protein AP2. This section of PI3K has the ability to trigger a cellular process that draws certain molecules into the cell, and it does so without requiring the enzyme’s usual lipid-modification function.
When the researchers interfered with the binding, the altered p85β did not perform its intended function. Instead of regulating cell movement through its braking mechanism, it accumulated in specific areas within the cell.
This results in cells moving more rapidly and persistently, indicating a lack of control over cell migration by the brake mechanism.
“Surprisingly, this single PI3K enzyme has both accelerator and brake pedals incorporated into its molecular structure,” Matsubayashi added. “The endocytic mechanism helps to regulate PI3K’s activity, ensuring that cell movement is controlled at the appropriate times and in the correct locations for essential biological processes.”
The specific braking function was discovered to be associated with the p85β subunit only. And because the p85β subunit of PI3K is linked to cancer-promoting properties, a deeper understanding of PI3K regulation is crucial.The specificity of its isoforms could potentially lead to innovative treatment approaches by selectively targeting the cancerous aspects of PI3K while maintaining the normal functions of PI3K in healthy cells.
