Dipartimento di Biologia e Patologia Molecolare e Cellulare, Università Federico II, Naples, Italy.
J Biol Chem. 2010 Dec 10;285(50):39260-70. doi: 10.1074/jbc.M110.174706. Epub 2010 Oct 5.
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.
PTPD1 是一种细胞质非受体蛋白酪氨酸磷酸酶，能刺激 Src-EGF 转导途径。PTPD1 在肌动蛋白细胞骨架和黏附部位的定位对于细胞分散和迁移是必需的。在这里，我们发现，在 EGF 刺激期间，PTPD1 迅速被招募到含有 EGF 受体的内体小泡中。PTPD1 的内体定位是通过与 KIF16B 相互作用介导的，KIF16B 是一种调节质膜上受体再循环的内体驱动蛋白。PTPD1 的沉默促进了 EGF 受体的降解，并抑制了下游 ERK 信号转导。我们还发现，PTPD1 在膀胱癌组织样本中明显增加。PTPD1 水平与这些肿瘤的分级和侵袭潜能呈正相关。过表达无活性的 PTPD1 突变体或内源性 PTPD1 的基因敲低严重抑制了人膀胱癌细胞的生长和迁移。这些发现确定了 PTPD1 是影响 EGF 受体稳定性以及膀胱癌细胞生长和迁移的内吞机制的一个新组成部分。
