Cells rely on outward-facing receptors as their ‘eyes and ears’ for detecting essential external signals. After activation, many receptors are internalized within small membrane bubbles called vesicles to deliver the receptors to endosomes, which either shuttle those receptors to degradation machinery or return them to the outer membrane in a ‘recycling’ process.
This endocytic mechanism is facilitated by clathrin proteins, which get recruited to nascent vesicles by adaptor proteins. AP-2 is among the more commonly used adaptors, but epidermal growth factor receptor (EGFR)—a signaling protein with a prominent role in many cancers—appears to be internalized largely by an AP-2-independent mechanism.
Wanjin Hong’s team at the A*STAR Institute of Molecular and Cell Biology, Singapore, previously characterized the Tom1 protein as a clathrin-recruiting molecule, and has now revealed another member of the same protein family, Tom1L1, as a specific adaptor for EGFR endocytosis1. According to Hong, this molecule has already been noted for its association with the Src cellular signaling pathway, and his team determined that Tom1L1 undergoes Src-mediated chemical modification in response to EGFR activation. Tom1L1 appears to interact with the receptor via other associated signaling factors, and is thus actively recruited from the cytoplasm—where it normally resides—to the cell membrane within minutes of EGFR activation.
Mutations that blocked the ability of Tom1L1 to interact with the Src pathway or to receive appropriate modification interfered with endocytosis and degradation of activated EGFR, with the receptor remaining largely localized to the cell surface (Fig. 1). Under these conditions, EGFR was eventually internalized at a significantly reduced pace, suggesting that Tom1L1 is involved at the early stages of endocytosis. Accordingly, Hong’s team was able to identify a previously unknown protein motif in Tom1L1 that directly interacts with and enables recruitment of clathrin.
These findings represent an advance for two heavily studied areas of biology, according to Hong. “So much has been published regarding endocytosis and EGFR,” he says, “and the discovery of Tom1L1 as a regulated adaptor for EGF-stimulated endocytosis of EGFR is significant in basic cell biology as well as signaling and cancer biology.” Based on this data, his team has already assembled a model that describes the mechanism of Tom1L1 adaptor function.
It also seems likely that this protein may modulate additional targets, given preliminary data revealing Tom1L1 activation in response to cellular growth factors besides EGF. “We are thinking about whether Tom1L1 is also involved in regulating endocytosis and/or signaling of other receptors,” says Hong.
The A*STAR-affiliated authors in this highlight are from the Institute of Molecular and Cell Biology.