PRL3 Promotes Cell Invasion and Proliferation by Down-regulation of Csk Leading to Src Activation

Fubo Liang,Jiao Liang,Wei-Qing Wang,Jin-Peng Sun,Eshwar Udho,Zhong-Yin Zhang

doi:10.1074/jbc.m608940200

Abstract

Phosphatase of regenerating liver 3 (PRL3) is overexpressed in a variety of tumors, and high levels of PRL3 expression are associated with tumorigenesis and metastasis. Consistent with an oncogenic role for PRL3, we show that ectopic PRL3 expression promotes cell proliferation and invasion. However, little is known about the molecular basis for PRL3 function. Obtaining this knowledge is vital for understanding PRL3-mediated disease processes and for the development of novel anticancer therapies targeted to PRL3. Here we report that up-regulation of PRL3 activates the Src kinase, which initiates a number of signal pathways culminating in the phosphorylation of ERK1/2, STAT3, and p130(Cas). The activation of these pathways likely contributes to the increased cell growth and motility of PRL3 cells. We provide evidence that PRL3 induces Src activation through down-regulation of Csk, a negative regulator of Src. Importantly, Src activation and Csk down-regulation are also observed in colon cancer cells expressing a higher level of PRL3. Thus, we have revealed a biochemical mechanism for the PRL3-mediated cell invasion and proliferation in which elevated PRL3 expression causes a reduction in Csk level, leading to Src activation.

Highlights

Phosphatase of regenerating liver 3 (PRL3) has attracted much attention because of its involvement in tumor metastases [7, 8]
Using a standard Transwell assay to measure cell migration toward serum, we found that 37% (1.85 ϫ 105 cells) of the PRL3(1) and 18% (8.88 ϫ 104 cells) of PRL3(2) cells reached the bottom chamber within 16 h, whereas less than 1% (ϳ5 ϫ 103 cells) of the vector control and PRL3/C104S cells migrated across the Transwell membrane (Fig. 2B)
In support for an oncogenic role for PRL3 in tumorigenesis and metastasis, we show that ectopic expression of PRL3 in human embryonic kidney 293 (HEK293) cells promotes cell proliferation and invasion

Summary

Introduction

PRL3 has attracted much attention because of its involvement in tumor metastases [7, 8]. Activated Src initiates a number of signal pathways, including the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and p130Cas, providing a likely mechanism by which PRL3 promotes cell migration and proliferation. Up-regulation of PRL3 Leads to Src Activation—As a first step toward elucidating the cellular pathways mediated by PRL3, we measured the total protein tyrosine phosphorylation of HEK293 cells expressing vector alone, PRL3, and PRL3/C104S using anti-Tyr(P) antibodies.

Results

Conclusion