Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization

PPTC7 is a mitochondrial phosphatase that is essential for mitochondrial biogenesis, metabolism, protein content maintenance and transport. Although the mitochondrial roles of PPTC7 are well characterized, its roles outside the mitochondria are unclear. Here we identified a non-mitochondrial role for PPTC7 in regulating epidermal growth factor receptor (EGFR) trafficking. PPTC7 interacts with and dephosphorylates VPS4A, a crucial ESCRT and multivesicular body-associated protein. We found that PPTC7-mediated dephosphorylation of VPS4A at serine 335 is required for VPS4A stability and its early endosomal localization. Either loss of PPTC7 or presence of constitutively phosphorylated VPS4A led to defective recycling of EGFR, thus leading to EGFR re-routing to lysosomes for degradation. Further, we demonstrate that PPTC7-VPS4A-dependent EGFR recycling promotes the AKT signaling pathway, thus enhancing cell proliferation and migration. Overall, our studies unveil an important mechanism where the PPTC7-VPS4A complex orchestrates an endosomal switch to promote EGFR recycling.