Catalytic domain of PRL-3 plays an essential role in tumor metastasis: Formation of PRL-3 tumors inside the blood vessels

PRL-3, a protein tyrosine phosphatase, has attracted much attention as its transcript is consistently upregulated in the process of colorectal cancer metastases to secondary organs. We studied mice injected via the tail vein with CHO cells stably expressing EGFP-tagged PRL-3 or catalytically inactive mutant PRL-3 (C104S). Our data showed that the EGFP-PRL-3-expressing cells rapidly induce metastatic tumor formation in lung, while EGFP-PRL-3 (C104S)-expressing cells lose this metastastic activity. Furthermore, detailed microscopic examinations revealed that some EGF-PRL-3-, but not EGFP-PRL-3 (C104S)-, expressing cells form micro- and macrometastatic solid tumors that sprout into blood vessels. Our studies provide clear evidence for a causative role of PRL-3 phosphatase activity in cancer metastasis and tumor-related angiogenesis events. The catalytic domain of PRL-3 could serve as an ideal therapeutic target for drug development to block the spread of colorectal cancer. Links to supplementary material: Video 1 Video 2 Video 3 Video 4 Video 5

[1]  P. Chavrier,et al.  Molecular Biology of the Cell , 1990, Color Atlas of Clinical Hematology.

[2]  K. Klinger,et al.  Alterations in Vascular Gene Expression in Invasive Breast Carcinoma , 2004, Cancer Research.

[3]  S. Semba,et al.  Expression of PRL-3 Phosphatase in Human Gastric Carcinomas: Close Correlation with Invasion and Metastasis , 2004, Pathobiology.

[4]  Qiang Xu,et al.  Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. , 2004, The American journal of pathology.

[5]  Weontae Lee,et al.  Structure of human PRL‐3, the phosphatase associated with cancer metastasis , 2004, FEBS letters.

[6]  C. Shou,et al.  The association of the expression level of protein tyrosine phosphatase PRL-3 protein with liver metastasis and prognosis of patients with colorectal cancer , 2004, Journal of Cancer Research and Clinical Oncology.

[7]  G. Kozlov,et al.  Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3* , 2004, Journal of Biological Chemistry.

[8]  K. Kinzler,et al.  PRL-3 expression in metastatic cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  M. Sulis,et al.  PTEN: from pathology to biology. , 2003, Trends in cell biology.

[10]  J. Li,et al.  PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. , 2003, Cancer research.

[11]  V. Bautch,et al.  Stem cell-derived endothelial cells/progenitors migrate and pattern in the embryo using the VEGF signaling pathway. , 2003, Developmental Biology.

[12]  B. Alberts,et al.  Molecular Biology of the Cell (4th Ed) , 2002 .

[13]  Jing Wang,et al.  The Tyrosine Phosphatase PRL-1 Localizes to the Endoplasmic Reticulum and the Mitotic Spindle and Is Required for Normal Mitosis* , 2002, The Journal of Biological Chemistry.

[14]  G. Kozlov,et al.  1H, 13C and 15N resonance assignments of the human phosphatase PRL-3. , 2002, Journal of biomolecular NMR.

[15]  J. Waxman,et al.  Analysis of stromal-epithelial interactions in prostate cancer identifies PTPCAAX2 as a potential oncogene. , 2002, Cancer letters.

[16]  P G Drake,et al.  Structural and Evolutionary Relationships among Protein Tyrosine Phosphatase Domains , 2001, Molecular and Cellular Biology.

[17]  Michael A. Choti,et al.  A Phosphatase Associated with Metastasis of Colorectal Cancer , 2001, Science.

[18]  J. Dixon,et al.  Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. , 2001, Biochemical and biophysical research communications.

[19]  K. Kinzler,et al.  Genes expressed in human tumor endothelium. , 2000, Science.

[20]  H. Horstmann,et al.  Prenylation-dependent Association of Protein-tyrosine Phosphatases PRL-1, -2, and -3 with the Plasma Membrane and the Early Endosome* , 2000, The Journal of Biological Chemistry.

[21]  J. Segall,et al.  A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. , 2000, Cancer research.

[22]  J. Denu,et al.  Mechanistic Basis for Catalytic Activation of Mitogen-activated Protein Kinase Phosphatase 3 by Extracellular Signal-regulated Kinase* , 2000, The Journal of Biological Chemistry.

[23]  Y. Tan,et al.  Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. , 1998, Biochemical and biophysical research communications.

[24]  L. Liotta,et al.  General mechanisms of metastasis , 1997, Cancer.

[25]  D. Crowell,et al.  Prenylation of oncogenic human PTP(CAAX) protein tyrosine phosphatases. , 1996, Cancer letters.

[26]  R. Taub,et al.  PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth , 1994, Molecular and cellular biology.

[27]  J. Folkman,et al.  The role of angiogenesis in tumor growth. , 1992, Seminars in cancer biology.

[28]  J. Dixon,et al.  Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. , 1991, The Journal of biological chemistry.

[29]  S. Crooke,et al.  A murine model to evaluate the ability of in vitro clonogenic assays to predict the response to tumors in vivo. , 1988, Cancer research.

[30]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[31]  I. Fidler,et al.  Critical determinants of cancer metastasis: rationale for therapy , 1999, Cancer Chemotherapy and Pharmacology.

[32]  J. Folkman,et al.  Angiogenic factors. , 1987, Science.