PTPD1 Supports Receptor Stability and Mitogenic Signaling in Bladder Cancer Cells

Annalisa Carlucci,Monia Porpora,Corrado Garbi,Mario Galgani,Margherita Santoriello,Massimo Mascolo,Domenico Di Lorenzo,Vincenzo Altieri,Maria Quarto,Luigi Terracciano,Max E Gottesman,Luigi Insabato,Antonio Feliciello

doi:10.1074/jbc.m110.174706

Abstract

PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src-EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells.

Highlights

Nance of mitochondrial membrane potential and ATP oxidative synthesis (8 –10)
We show that PTPD1 is a novel component of the endocytic pathway that supports EGF receptor stability and mitogenic signaling
We show that PTPD1, an activator of Src tyrosine kinase, is a newly identified component of the endocytic pathway

Summary

Introduction

Nance of mitochondrial membrane potential and ATP oxidative synthesis (8 –10). When not in complex with AKAP121, PTPD1 directs EGF/Src signaling to the nucleus, activating ERK1/2- and Elk1-dependent gene transcription [3]. PTPD1 is required for growth and motility of urothelial cancer cells in vitro, and its expression in human bladder cancer tissue positively correlates with tumor stage and invasive potential. To show that PTPD1, localizes within or is associated with endosomes, we stimulated cells with EGF and performed immunostaining analysis with antibodies directed against different endosome components.

Results

Conclusion