Abstract
Tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase that negatively regulates growth factor-induced survival signalling. Here, we demonstrate that PTEN attenuates epidermal growth factor receptor (EGFR) signalling by promoting late endosome maturation by virtue of its protein phosphatase activity. Loss of PTEN impairs the transition of ligand-bound EGFR from early to late endosomes. We unveil Rab7, a critical GTPase for endosome maturation, as a functional PTEN interacting partner. PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. Thus, our findings reveal PTEN-dependent endosome maturation through phosphoregulation of Rab7 as an important route of controlling EGFR signalling.
Highlights
Tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase that negatively regulates growth factor-induced survival signalling
Further we demonstrate that PTEN dephosphorylates Rab[7] and regulates its localization to the late endosomal membranes, which is critical for endosome maturation
These results showed that trafficking of EGF from early to late endosomes was hampered on PTEN depletion
Summary
Tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase that negatively regulates growth factor-induced survival signalling. We demonstrate that PTEN attenuates epidermal growth factor receptor (EGFR) signalling by promoting late endosome maturation by virtue of its protein phosphatase activity. Our findings reveal PTEN-dependent endosome maturation through phosphoregulation of Rab[7] as an important route of controlling EGFR signalling. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is an important tumour suppressor, which functions in many cellular processes such as cell proliferation, survival, growth, metabolism, migration and apoptosis[1,2,3]. Role of PTEN in endocytic trafficking pathway of growth factor receptors is unknown. We show that PTEN controls endocytic trafficking of EGFR by promoting late endosome maturation. Further we demonstrate that PTEN dephosphorylates Rab[7] and regulates its localization to the late endosomal membranes, which is critical for endosome maturation
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