Frosi et al. describe a new mechanism for turning down epidermal growth factor receptor (EGFR) activity that dispatches the protein for destruction.
Through its kinase activity, EGFR is crucial for cell division, survival, and movement. But faulty or overactive EGFR abets many cancers. Several cellular controls keep EGFR in check. After the receptors are stimulated, for example, endocytosis abducts them from the cell surface. Alternatively, a protein called RALT blocks EGFR's activity by clamping onto its kinase domain. But RALT sometimes follows internalized receptors into the cell, an unexpected behavior because kinase activity is necessary for EGFR endocytosis. Frosi et al. wondered whether RALT could suppress EGFR yet drive its endocytosis.
The researchers discovered that RALT can trigger the receptor's endocytosis by maneuvering it into clathrin-coated pits. To move the receptor into position, RALT connects to two kinds of proteins—AP-2 and the intersectins—that transfer molecules into the pits and allow their maturation into vesicles.
RALT directs EGFR to the lysosomes for digestion. Proteins destined for destruction often carry ubiquitin tags, but the researchers showed that EGFR ubiquitylation wasn't required when RALT was involved. Thus to rapidly decrease EGFR signaling, RALT blocks the receptor's kinase activity. For a slower, longer-lasting effect, it also promotes the molecule's removal and destruction. A key question is RALT's role in cancer—a recent study pegged it as a tumor suppressor in the brain cancer glioblastoma.
