Lajoie et al. reveal. Which domain wins the competition for this division-promoting protein helps determine whether a cell becomes cancerous.
Creating one of the domains is Caveolin1 (Cav1), which congregates in plasma membrane indentations called caveolae. Cav1 clusters pen in EGFR molecules and block them from relaying progrowth signals into the cell. Cav1 is faulty or absent in many tumors. Another domain, the galectin lattice, forms when galectin molecules interlink glycoproteins on the cell surface. The enzyme Mgat5 promotes these connections by modifying the ends of the glycoproteins. The researchers previously showed that the lattice holds EGFR at the membrane and increases cells' sensitivity to growth stimulators such as epidermal growth factor (EGF).
In the current study, Lajoie et al. identified interactions between the two types of domains. The researchers found that in tumor cell lines that lack Mgat5, adding a little Cav1 squelched EGF signaling—and thus tumor growth—by trapping EGFR. Eliminating Cav1 from these cells restored their sensitivity to EGF. Tumor cells that make Mgat5 were also responsive to EGF. The results suggest that galectin lattices block Cav1's inhibition of EGFR.
The lattices interfered by restricting EGFR movement. The authors tracked the receptor's movements by photobleaching part of the membrane and following labeled EGFR molecules. If tumor cells had normal levels of Mgat5, EGFR was less likely to cozy up to Cav1 clusters than in cells lacking the enzyme.
Overall, the study indicates that the galectin lattice speeds tumor growth by capturing EGFR and preventing Cav1 domains from ensnaring the receptor and shutting it down. Because the lattice gets first dibs on the receptor, Cav1 serves as a tumor suppressor only when the lattice is down. The work also explains the mysterious observation that some of the most dangerous cancers produce copious Cav1: other molecules can override its ability to block growth.