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 p130Cas . 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.Protein-tyrosine phosphatases (PTPs) 2 are key regulatory enzymes in various signal transduction pathways (1). Defective or inappropriate regulation of PTP activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases, including cancer (2, 3). The PRL phosphatase represents a novel subfamily of PTPs, which is comprised of three members (PRL1, -2, and -3) sharing a high degree (Ͼ75%) of amino acid sequence identity (4 -6). PRL1 was originally identified as an immediate early gene in regenerating liver (4). Subsequently, the PRL phosphatases have been implicated in the development of a number of tumorigenesis and metastasis processes (7).PRL3 has attracted much attention because of its involvement in tumor metastases (7,8). PRL3 is consistently and massively overexpressed in liver metastases of colorectal cancer, and its expression in primary tumors and normal colorectal epithelium is undetectable (9). Subsequently, PRL3 mRNA is found to be elevated in nearly all metastatic lesions derived from colorectal cancers, regardless of the sites of metastasis (liver, lung, brain, or ovary) (10, 11). High PRL3 expression has also been reported in cancer types other than colorectal cancers. For example, PRL3 is highly expressed in a Hodgkin lymphoma cell line (12) and in liver carcinoma samples (13); high PRL3 expression has been detected in invasive breast tumor vasculature (14), and overexpression of PRL3 is associated with ovarian cancer progression (15). In addition, PRL3 promotes invasion and metastasis of human gastric carcinomas (16) and mouse melanoma (13). Moreover, cells (Chinese hamster ovary and B16) stably transfected with PRL3 exhibit enhanced motility and invasive activity and induce metastatic tumor formation in mice (13, 17), whereas knoc...

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Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.