Loss Of PTEN Promotes Formation Of Signaling-Specific Clathrin-Coated Pits

Despite the large number of cargo molecules that traffic through clathrin-coated pits (CCPs), it is not well understood whether signaling receptors activated in cancer, such as epidermal growth factor receptor (EGFR), are regulated through a specific subset of CCPs. The signaling lipid phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3), which is dephosphorylated by phosphatase tensin homolog (PTEN), is a potent tumorigenic signaling lipid that is present in excess in many types of cancers. We find PTEN and EGF bound EGFR are enriched in a distinct subset of short-lived CCPs that corresponded with clathrin-dependent EGF-induced signaling. We demonstrate that PTEN plays a role regulating CCP dynamics, where we find a larger proportion of shorted-lived CCPs and higher initiation density compared to the normal cells. Furthermore, increased PI(3,4,5)P3 results in higher proportion of short-lived CCPs, an effect that recapitulates PTEN deletion. Our findings provide strong evidence for the existence of short-lived ‘signaling-specific’ CCPs and demonstrates the importance of PTEN and PI(3,4,5)P3 in regulating CCP dynamics.