PRL1 promotes cell migration and invasion by increasing MMP2 and MMP9 expression through Src and ERK1/2 pathways.

The PRL (phosphatase of regenerating liver) phosphatases represent a distinct class of protein tyrosine phosphatases, which are implicated in tumorigenesis and metastasis processes. Accumulating evidence indicates that alteration of PRL1 expression affects cell motility and tumor metastasis, although the biochemical pathways regulated by PRL1 remain less well defined. We find that elevated expression of PRL1 increases the levels of the matrix metalloproteinases MMP2 and MMP9.

Translational control of C-terminal Src kinase (Csk) expression by PRL3 phosphatase.

Phosphatase of regenerating liver 3 (PRL3) is up-regulated in cancer metastases. However, little is known of PRL3-mediated cellular signaling pathways. We previously reported that elevated PRL3 expression increases Src kinase activity, which likely contributes to the increased tumorigenesis and metastasis potential of PRL3.

Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for PRL1-mediated cell growth and migration.

The phosphatase of regenerating liver (PRL) phosphatases are implicated in a number of tumorigenesis and metastasis processes. The PRLs are unique among protein-tyrosine phosphatases in that they have extremely low phosphatase activity, a high propensity for trimer formation, and a polybasic region that precedes the C-terminal prenylation motif. To investigate the functional significance of these distinctive biochemical and structural features, we established a cell-based system in which ectopic PRL1 expression increased cell proliferation and migration, whereas knockdown of endogenous PRL1 abrogated these cellular activities.

Proteomic approaches to studying protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that play key roles in cell signaling. Deregulation of PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. Since phosphate removal by the PTPs can both enhance and antagonize cellular signaling, it is essential to elucidate the physiological context in which PTPs operate.

PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation.

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.

Global analysis of protein tyrosine phosphatase activity with ultra-sensitive fluorescent probes.

Protein tyrosine phosphatases (PTPs) consist of a large family of enzymes known to play important roles in controlling virtually all aspects of cellular processes. However, assigning functional significance of PTPs in normal physiology and in diseases remains a major challenge in cell signaling. Since the function of a PTP is directly associated with its intrinsic activity, which is subject to post-translational regulation, new tools are needed to monitor the dynamic activities of PTPs, rather than mere abundance, on a global scale within the physiologically relevant environment of cells.

ErbB3-dependent motility and intravasation in breast cancer metastasis.

A better understanding of how epidermal growth factor receptor family members (ErbBs) contribute to metastasis is important for evaluating ErbB-directed therapies. Activation of ErbB3/ErbB2 heterodimers can affect both proliferation and motility. We find that increasing ErbB3-dependent signaling in orthotopic injection models of breast cancer can enhance intravasation and lung metastasis with no effect on primary tumor growth or microvessel density.

Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis.

Although overexpression of the epidermal growth factor receptor (EGFR; ErbB1) has been correlated with poor prognosis in breast and other cancers, clinical trials of ErbB1 inhibitors have shown limited efficacy in inhibiting tumor proliferation. To evaluate other possible roles of ErbB1 in tumor malignancy besides proliferation, we have developed a series of tools for analysis of intravasation. Overexpression of ErbB1 in MTLn3 mammary adenocarcinoma cells results in increased intravasation and lung metastasis from tumors formed by injection of cells in the mammary fat pad.

Structure and biochemical properties of PRL-1, a phosphatase implicated in cell growth, differentiation, and tumor invasion.

The PRL (phosphatase of regenerating liver) phosphatases constitute a novel class of small, prenylated phosphatases that are implicated in promoting cell growth, differentiation, and tumor invasion, and represent attractive targets for anticancer therapy. Here we describe the crystal structures of native PRL-1 as well as the catalytically inactive mutant PRL-1/C104S in complex with sulfate. PRL-1 exists as a trimer in the crystalline state, burying 1140 A2 of accessible surface area at each dimer interface.

The role of protein-tyrosine phosphatase 1B in integrin signaling.

Protein-tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling and a novel therapeutic target for the treatment of type 2 diabetes, obesity, and other associated metabolic syndromes. Because PTP1B regulates multiple signal pathways and it can both enhance and antagonize a cellular event, it is important to establish the physiological relevance of PTP1B in these processes. In this study, we utilize potent and selective PTP1B inhibitors to delineate the role of PTP1B in integrin signaling.

Small molecule approach to studying protein tyrosine phosphatase.

Understanding the function of protein tyrosine phosphatases (PTPs) is crucial to deciphering cellular signaling in higher organisms. Of the 100 putative PTPs in human genome, only a little is known about their precise biological functions. Thus establishing novel ways to study PTP function remains a top priority among researchers.

Activity-based probes for protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are involved in the regulation of many aspects of cellular activity including proliferation, differentiation, metabolism, migration, and survival. Given the large number and complexity of PTPs in cell signaling, new strategies are needed for the integrated analysis of PTPs in the whole proteome. Unfortunately, the activities of many PTPs are tightly regulated by posttranslational mechanisms, limiting the utility of standard genomics and proteomics methods for functional characterization of these enzymes.

Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague.

Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to Bubonic Plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. YopH is an essential virulence factor whose protein-tyrosine phosphatase (PTP) activity is required for Yersinia pathogenicity.

CD157 undergoes ligand-independent dimerization and colocalizes with caveolin in CHO and MCA102 fibroblasts.

CD157, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, has recently been shown to induce protein tyrosine phosphorylation in monocytes differentiated from HL-60 cells (mHL-60) in a ligand-dependent manner, but in a ligand-independent manner in stable CD157-transfected CHO (CHO/CD157) and MCA102 (MCA/CD157) fibroblasts [Cell Signal. 11 (1999) 891-897.].