Protein Tyrosine Phosphatase Kappa Research Articles

P-235 Elevated protein tyrosine phosphatase kappa expression is associated with disease progression and poor prognosis of pancreatic cancer

Protein tyrosine phosphatase kappa (PTPRK) is a phosphatase which is recognised as a tumour suppressor. PTPRK can promote the internalization of ZNRF3 by dephosphorylating CD133. It is a negative regulator of the invasion and adhesion of breast cancer cells, what is more, it is also enhance the activation of STAT3 in lung cancer. Pancreatic exocrine cancer is an extremely aggressive tumour with a mortality being nearly equal to its incidence. The aim of present study is to assess the involvement of PTPRK in the disease progression of pancreatic cancer. PTPRK transcripts were determined in pancreatic cancers (n=201) and adjacent non-tumour pancreatic tissues (n=201) using real time PCR. The pancreatic tissue samples were collected immediately after surgery at Peking University Cancer Hospital. All procedures used are approved by the Peking University Cancer Hospital Research Ethics Committee. The implication of PTPRK in disease progression and prognosis was analysed which was also further supported by analyses of RNAseq data of pancreatic cancer (The Cancer Genome Atlas, TCGA_PAAD) and a gene array data (GSE15471 and GSE71729). Further bioinformatic analysis has been done to determine which pathway is regulated by PTPRK. Both the public dataset GSE15471 and the Beijing clinical cohort shows increased PTPRK expression in the tumours compared with adjacent normal tissue. PTPRK expression in tumours of the earliest stage (T1) is lower than more invasive tumours (T2, T3 and T4). However, PTPRK tends to be lower in primary tumours that presented lymph node metastases. There is no significant change of PTPRK expression in the primary tumours that developed distant metastases. Moreover, PTPRK is down regulated in distant metastatic tumours from pancreatic cancer (GSE71729). Compared with lesions in the tail of pancreas, the PTPRK has also been found has a higher expression level in pancreatic head and body. Pancreatic cancer patients with a higher PTPRK level had poor overall and relapse free survival compared with patients with tumours of low PTPRK expression. In the TCGA PAAD cohort, PTPRK is positively correlated with some RTKs family gene, including EGFR, KDR, FGF and PDGF. However, neither protein level of EGFR nor phosphorylation of EGFR (Y1068 and Y1173) presented obvious difference according to PTPRK transcripts in the corresponding tumours. The PTPRK is involved in pancreatic cancer progression, it is associated with a poor prognosis. Exact role played by PTPRK in pancreatic cancer and its predictive and therapeutic potential are yet to be fully investigated using both in vitro and in vivo models.

The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-κB, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities.

Analysis of PTPRK polymorphisms in association with risk and age at onset of Alzheimer's disease, cancer risk, and cholesterol

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10−6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10−2 and 5.18 × 10−3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10−2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10−4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10−3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10−3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10−3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10−5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors.

A potential role may be played by receptor-type protein tyrosine phosphatase kappa (PTPRK) in angiogenesis due to its critical function in coordinating intracellular signal transduction from various receptors reliant on tyrosine phosphorylation. In the present study, we investigated the involvement of PTPRK in the cellular functions of vascular endothelial cells (HECV) and its role in angiogenesis using in vitro assays and a PTPRK knockdown vascular endothelial cell model. PTPRK knockdown in HECV cells (HECVPTPRKkd) resulted in a decrease of cell proliferation and cell-matrix adhesion; however, increased cell spreading and motility were seen. Reduced focal adhesion kinase (FAK) and paxillin protein levels were seen in the PTPRK knockdown cells which may contribute to the inhibitory effect on adhesion. HECVPTPRKkd cells were more responsive to the treatment of fibroblast growth factor (FGF) in their migration compared with the untreated control and cells treated with VEGF. Moreover, elevated c-Src and Akt1 were seen in the PTPRK knockdown cells. The FGF-promoted cell migration was remarkably suppressed by an addition of PLCγ inhibitor compared with other small inhibitors. Knockdown of PTPRK suppressed the ability of HECV cells to form tubules and also impaired the tubule formation that was induced by FGF and conditioned medium of cancer cells. Taken together, it suggests that PTPRK plays dual roles in coordinating angiogenesis. It plays a positive role in cell proliferation, adhesion and tubule formation, but suppresses cell migration, in particular, the FGF-promoted migration. PTPRK bears potential to be targeted for the prevention of tumour associated angiogenesis.

Quantitative analysis of low-abundance serological proteins with peptide affinity-based enrichment and pseudo-multiple reaction monitoring by hybrid quadrupole time-of-flight mass spectrometry

Multiple reaction monitoring (MRM) is commonly used for the quantitative analysis of proteins during mass pectrometry (MS), and has excellent specificity and sensitivity for an analyte in a complex sample. In this study, a pseudo-MRM method for the quantitative analysis of low-abundance serological proteins was developed using hybrid quadrupole time-of-flight (hybrid Q-TOF) MS and peptide affinity-based enrichment. First, a pseudo-MRM-based analysis using hybrid Q-TOF MS was performed for synthetic peptides selected as targets and spiked into tryptic digests of human serum. By integrating multiple transition signals corresponding to fragment ions in the full scan MS/MS spectrum of a precursor ion of the target peptide, a pseudo-MRM MS analysis of the target peptide showed an increased signal-to-noise (S/N) ratio and sensitivity, as well as an improved reproducibility. The pseudo-MRM method was then used for the quantitative analysis of the tryptic peptides of two low-abundance serological proteins, tissue inhibitor of metalloproteinase 1 (TIMP1) and tissue-type protein tyrosine phosphatase kappa (PTPκ), which were prepared with peptide affinity-based enrichment from human serum. Finally, this method was used to detect femtomolar amounts of target peptides derived from TIMP1 and PTPκ, with good coefficients of variation (CV 2.7% and 9.8%, respectively), using a few microliters of human serum from colorectal cancer patients. The results suggest that pseudo-MRM using hybrid Q-TOF MS, combined with peptide affinity-based enrichment, could become a promising alternative for the quantitative analysis of low-abundance target proteins of interest in complex serum samples that avoids protein depletion.

Protein tyrosine phosphatase kappa (PTPRK) is a negative regulator of adhesion and invasion of breast cancer cells, and associates with poor prognosis of breast cancer

Receptor-like protein tyrosine phosphatase kappa (PTPRK) has been shown to exhibit homophilic binding. It is a putative tumour suppressor in primary central nervous system lymphomas and colorectal cancer. The present study investigated the expression of PTPRK in breast cancer and the biological impact of PTPRK on breast cancer cells. Expression of PTPRK protein and gene transcript was examined in a cohort of breast cancer patients. The association of PTPRK transcript level and pathological and clinical aspects was then analysed. Knockdown of PTPRK in breast cancer cells was performed using a specific anti-PTPRK transgene. The impact of PTPRK knockdown on breast cancer cells was investigated using in vitro cell function assays. Lower levels of PTPRK transcripts were seen in the advanced breast cancer. The reduced PTPRK transcript levels were associated with poor prognosis of the disease. PTPRK transcript levels were decreased in the primary tumours of patients who died from breast cancer or had metastases. Patients with lower expression of PTPRK had shorter survival compared with those higher expression levels of PTPRK. Knockdown of PTPRK resulted in increased proliferation, adhesion, invasion, and migration of breast cancer cells in vitro. Decreased expression of PTPRK in breast cancer is correlated with poor prognosis. PTPRK is a negative regulator of adhesion, invasion, migration, and proliferation of breast cancer cells. This suggests that PTPRK is a potential tumour suppressor in breast cancer.

P2-05-05: Receptor-Like Protein Tyrosine Phosphatase Kappa (PTPRK) and Its Biological Role in Angiogenesis.

Abstract Introduction: Protein Tyrosine Phosphatases (PTPs) are known as signalling molecules which affect cell growth, differentiation and oncogenic transformation. PTPs have been indicated in tumourigenesis and progression of various solid tumours. PTPRK, receptor-type protein tyrosine phosphatase kappa, has been shown to down-regulate transcriptional activity of beta-catenin and impact distribution of beta-catenin/E-cadherin complexes on cancer cell membrane. However, the role played by PTPRK in angiogenesis remains unknown. In present study, the effect of PTPRK knock-down on functions and tubule formation ability of HECV cells was investigated. (or In the present study, the effect of PTPRK on angiogenesis process was investigated.) Methods: anti-PTPRK ribozyme transgenes were constructed to knock-down PTPRK expression in vascular endothelial cells, HECV cells. The subsequent effect upon in vitro cell growth, adhesion, migration and microvascular tubule formation was examined using a variety of functional assays. Result: Knock-down PTPRK in HECV cells (HECVΔPTPRK) resulted in a decrease of cell growth in vitro. The growth rate of HECVΔPTPRK was 276.3±16.4, p=0.01 compared with HECVpEF (314.8±21.9) controls. However, knock-down of PTPRK in HECV cells increased cell motility. The cell migration distance of HECVΔPTPRK was 83.8±19.8μm, p=0.008 compared with HECVpEF (61.8±11.8μm) controls. No effect on cell adhesion by PTPRK knockdown was seen in HECVΔPTPRK (81.2±6.6), compared with HECVpEF control (78.8±15.6). Furthermore, knock-down of PTPRK suppressed tubule formation in HECV cells, the length of total tubules (μm) in HECVΔPTPRK was 2167.4±943.2, p&amp;lt;0.05 compared with HECVpEF (3130.6±386.9) control. Conclusion: Knock-down of PTPRK reduced the growth and tubule formation abilities of vascular endothelial cells. It suggests that PTPRK is pivotal regulator for angiogenic process. Further investigations are required to identify the downstream pathways involved in these impacts. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-05.

The Lysyl Oxidase Propeptide Interacts with the Receptor-Type Protein Tyrosine Phosphatase Kappa and Inhibits β-Catenin Transcriptional Activity in Lung Cancer Cells

The propeptide region of the lysyl oxidase proenzyme (LOX-PP) has been shown to inhibit Ras signaling in NIH 3T3 and lung cancer cells with activated RAS, but its mechanism of action is poorly understood. Here, a yeast two-hybrid assay of LOX-PP-interacting proteins identified a clone encoding the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP-κ), and the interaction of the two proteins in mammalian cells was confirmed. RPTP-κ is proteolytically processed to isoforms that have opposing effects on β-catenin activity. The RPTP-κ transmembrane P subunit interacts with and sequesters β-catenin at the cell membrane, where it can associate with E-cadherin and promote intercellular interactions. At high cell density, further processing of the P subunit yields a phosphatase intracellular portion (PIC) subunit, which chaperones β-catenin to the nucleus, where it can function to activate transcription. Lung cancer cells were found to contain higher PIC levels than untransformed lung epithelial cells. In H1299 lung cancer cells, ectopic LOX-PP expression reduced the nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing the nuclear levels and transcriptional activity of β-catenin while increasing β-catenin membrane localization. Thus, LOX-PP is shown to negatively regulate pro-oncogenic β-catenin signaling in lung cancer cells.

Galectin-3 binding protein promotes cell motility in colon cancer by stimulating the shedding of protein tyrosine phosphatase kappa by proprotein convertase 5

It has previously been reported that shedding of the PTPκ ectodomain drives enhanced motility of colon cancer cells. Herein, we provide mechanism underlying the regulation of PTPκ shedding by galectin-3 binding protein. PTPκ was inarguably scissored by the processed form of proprotein convertase 5 (subtilisin/kexin type 5), and galectin-3 binding protein which is over-produced in colon cancer cells and tissues contributed to increased cancer cell motility by acting as a negative regulator of galectin-3 at the cell surface. The high expression ratio of galectin-3 binding protein to galectin-3 was clinically correlated to lymphatic invasion. These results suggest that galectin-3 binding protein may be a potential therapeutic target for treatment of, at least, colon cancer patients with high expression of galectin-3 binding protein.

The effect of receptor protein tyrosine phosphatase kappa on the change of cell adhesion and proliferation induced by N‐acetylglucosaminyltransferase V

N-acetylglucosaminyltransferase V (GnT-V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT-V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPkappa) but also decreased its protein level. Moreover, GnT-V overexpression decreased cell calcium-independent adhesion and increased the tyrosine phosphorylation level of beta-catenin, in which RPTPkappa played an important role. Since RPTPkappa has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPkappa on the change of cell adhesion and beta-catenin signaling induced by GnT-V. Our results showed that preventing RPTPkappa cleavage rescued the above effects of GnT-V, suggesting that furin cleavage could be one of the factors for RPTPkappa to regulate cell adhesion and beta-catenin signaling in GnT-V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of beta-catenin was associated with the increased nuclear level of beta-catenin and downstream signaling molecules such as c-myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT-V could decrease human hepatoma SMMC-7721 cell adhesion and promote cell proliferation partially through RPTPkappa.

EGF-mediated migration signaling activated by N-acetylglucosaminyltransferase-V via receptor protein tyrosine phosphatase kappa

N-acetylglucosaminyltransferase-V (GnT-V) has been reported to be closely associated with tumor migration, but the mechanism has been not currently clear. In this study we found that GnT-V activated EGFR signaling and promoted cell migration through receptor protein tyrosine phosphatase kappa (RPTPκ). The overexpression of GnT-V gene in human hepatoma SMMC-7721 cell line not only induced the addition of β1,6 GlcNAc branch to N-glycan of RPTPκ but also decreased the protein level of RPTPκ, which both contributed to the decreased phosphatase activity of RPTPκ activating subsequently EGFR signaling. Moreover, we found that the knockdown of RPTPκ and its addition of β1,6 GlcNAc branch both promoted cell migration, which could be ascribed to the activation of EGFR signaling regulated by RPTPκ. Therefore, our findings could provide an insight into the molecular mechanism of how GnT-V promoted cell migration, suggesting that RPTPκ could be one of factors regulating the EGF-mediated migration signals.

A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat

Bone marrow (BM)-derived T-cell progenitors differentiate into CD4 or CD8 single-positive (SP) cells in the thymus. We have previously reported that a single autosomal mutation, thid, causes a defect in the maturation of CD4 SP thymocytes and an abnormality of peripheral helper T cells in the LEC rat. In this study we attempted to identify a gene responsible for the thid mutation. We first performed genetic linkage analysis and mapped the thid locus between Myb and D1Rat392 on Chr 1. In this region we found an approximately 380-kb deletion from intron 3 of the Ptprk gene, which encodes a receptor-like protein tyrosine phosphatase type kappa (RPTPkappa) to intron 1 of the RGD1560849 predicted gene in the LEC rat genome. Reconstitution with syngenic BM cells transduced Ptprk but not the RGD1560849 predicted gene rescued development of CD4 SP cells in the LEC rat thymus. It is confirmed by this result that the Ptprk gene is responsible for the thid mutation in the LEC rat. Our results further suggest that RPTPkappa plays a critical role in the development of CD4 SP cells in the thymus.

Identification of target proteins of N‐acetylglucosaminyl transferase V in human colon cancer and implications of protein tyrosine phosphatase kappa in enhanced cancer cell migration

To gain a better understanding of the mechanism underlying colon cancer and to search for potential markers of colon cancer prognosis, a comparative proteomic analysis of colon cancer WiDr cells was conducted using 2-DE and lectin blot, followed by identification based on ESI-MS. Through these approaches 14 proteins were identified as candidate target proteins for N-acetylglucosaminyl transferase V (GnT-V) that would be expected to be implicated in the progression of colon cancer. We selected protein tyrosine phosphatase kappa (PTPkappa) as a model protein to validate this approach to the discovery of novel biomarkers in colon cancer. PTPkappa underwent an aberrant glycosylation in GnT-V-overexpressing WiDr cells, and the aberrantly glycosylated PTPkappa was vulnerable to proteolytic cleavage. The enhanced cleavage of PTPkappa in GnT-V-overexpressing cells was responsible for the mitigation of the homophilic binding capacity, resulting in an increase in cancer cell migration.

Transforming Growth Factor β (TGF-β)-Smad Target Gene Protein Tyrosine Phosphatase Receptor Type Kappa Is Required for TGF-β Function

Transforming growth factor beta (TGF-beta) inhibits proliferation and promotes cell migration. In TGF-beta-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-beta up-regulated PTPRK mRNA and RPTPkappa (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-beta-mediated antimitogenesis. Endogenous RPTPkappa associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-beta enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTPkappa was eliminated by RNA interference (RNAi). In cells expressing RPTPkappa RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTPkappa positively regulates Src; (ii) HER2 signaling and TGF-beta-induced RPTPkappa converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTPkappa is required for both the antiproliferative and the promigratory effects of TGF-beta.

Receptor Protein Tyrosine Phosphatase μ Regulates the Paracellular Pathway in Human Lung Microvascular Endothelia

The pulmonary vascular endothelial paracellular pathway and zonula adherens (ZA) integrity are regulated, in part, through protein tyrosine phosphorylation. ZA-associated protein tyrosine phosphatase (PTP)s are thought to counterregulate tyrosine phosphorylation events within the ZA multiprotein complex. One such receptor PTP, PTPmu, is highly expressed in lung tissue and is almost exclusively restricted to the endothelium. We therefore studied whether PTPmu, in pulmonary vascular endothelia, associates with and/or regulates both the tyrosine phosphorylation state of vascular endothelial (VE)-cadherin and the paracellular pathway. PTPmu was expressed in postconfluent human pulmonary artery and lung microvascular endothelial cells (ECs) where it was almost exclusively restricted to EC-EC boundaries. In human lung microvascular ECs, knockdown of PTPmu through RNA interference dramatically impaired barrier function. In immortalized human microvascular ECs, overexpression of wild-type PTPmu enhanced barrier function. PTPmu-VE-cadherin interactions were demonstrated through reciprocal co-immunoprecipitation assays and co-localization with double-label fluorescence microscopy. When glutathione S-transferase-PTPmu was incubated with purified recombinant VE-cadherin, and when glutathione S-transferase-VE-cadherin was incubated with purified recombinant PTPmu, PTPmu directly bound to VE-cadherin. Overexpression of wild-type PTPmu decreased tyrosine phosphorylation of VE-cadherin. Therefore, PTPmu is expressed in human pulmonary vascular endothelia where it directly binds to VE-cadherin and regulates both the tyrosine phosphorylation state of VE-cadherin and barrier integrity.

Molecular and genetic features of a labeled class of spinal substantia gelatinosa neurons in a transgenic mouse

Genetic incorporation in a mouse of a transgene containing the prion promoter and the green fluorescent protein (GFP) coding sequence labels a set of substantia gelatinosa (SG) neurons (SG-GFP) homogenous in morphology, electrophysiology, and gamma-amino-butyric acid expression. In the present analysis the SG-GFP neurons are established to have protein kinase C-betaII immunoreactivity and to lack evidence for the presence of calbindin D-28k, parvalbumin, and protein kinase C-gamma. These neurons were hyperpolarized by mediators of descending control, norepinephrine and serotonin. Sequential polymerase chain reactions established the insertion of the transgene to be in the receptor protein tyrosine phosphatase kappa (RPTP-kappa) and the laminin receptor 1 (ribosomal protein SA) pseudogene 1 locus. RPTP-kappa expression in both GFP-labeled dorsal root ganglia and SG neurons raises the possibility that homophilic interactions of RPTP-kappa contribute to establishment of connections between specific classes of primary afferent and SG neurons.

Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse

Receptor protein tyrosine phosphatases (RPTPs) comprise a family of proteins that feature intracellular phosphatase domains and an ectodomain with putative ligand-binding motifs. Several RPTPs are expressed in the brain, including RPTP-κ which participates in homophilic cell–cell interactions in vitro [Y.-P. Jiang, H. Wang, P. D'Eustachio, J.M. Musacchio, J. Schlessinger, J. Sap, Cloning and characterization of R-PTP-κ, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region, Mol. Cell. Biol. 13 (1993) 2942–2951; J. Sap, Y.-P. Jiang, D. Friedlander, M. Grumet, J. Schlessinger, Receptor tyrosine phosphatase R-PTP-κ mediates homophilic binding, Mol. Cell. Biol. 14 (1994) 1–9]. The homology of RPTP-κ's ectodomain to neural cell adhesion molecules indicates potential roles in developmental processes such as axonal growth and target recognition, as has been demonstrated for certain Drosophila RPTPs. The brain distribution of RPTP-κ-expressing cells has not been determined, however. In a gene-trap mouse model with a β-gal+neo (β-geo) insertion in the endogenous RPTP-κ gene, the consequent loss of RPTP-κ's enzymatic activity does not produce any obvious phenotypic defects [W.C. Skarnes, J.E. Moss, S.M. Hurtley, R.S.P. Beddington, Capturing genes encoding membrane and secreted proteins important for mouse development, Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 6592–6596]. Nevertheless, since the transgene's expression is driven by the endogenous RPTP-κ promoter, distribution of the truncated RPTP-κ/β-geo fusion protein should reflect the regional and cellular expression of wild-type RPTP-κ, and thus may identify sites where RPTP-κ is important. Towards that goal, we have used this mouse model to map the distribution of the truncated RPTP-κ/β-geo fusion protein in the adult mouse brain using β-galactosidase as a marker enzyme. Visualization of the β-galactosidase activity revealed a non-random pattern of expression, and identified cells throughout the CNS that display RPTP-κ promoter activity. Several neural systems highly expressed the transgene—most notably cortical, olfactory, hippocampal, hypothalamic, amygdaloid and visual structures. These well-characterized brain regions may provide a basis for future studies of RPTP-κ function.