PTPRK Research Articles

A Genome-Wide Association Study of Sprint Performance in Elite Youth Football Players

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leońska-Duniec, A, Pająk, B, Chycki, J, Moska, W, Lulińska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cięszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.

Author response: The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell–cell adhesion

Author response: The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell–cell adhesion

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.

Notch and TGF-β pathways cooperatively regulate receptor protein tyrosine phosphatase-κ (PTPRK) gene expression in human primary keratinocytes.

Receptor protein tyrosine phosphatase-κ (PTPRK) specifically and directly dephosphorylates epidermal growth factor receptor (EGFR), thereby limiting EGFR function in primary human keratinocytes. PTPRK expression is increased by the TGF-β/Smad3 pathway and cell-cell contact. Because the Notch receptor pathway is responsive to cell-cell contact and regulates keratinocyte growth and differentiation, we investigated the interplay between Notch and TGF-β pathways in regulation of PTPRK expression in human keratinocytes. Suppression of Notch signaling by γ-secretase inhibitors substantially reduced cell contact induction of PTPRK gene expression. In sparse keratinocyte cultures, addition of soluble Notch-activating ligand jagged one peptide (Jag1) induced PTPRK. Of interest, cell contact-induced expression of TGF-β1 and TGF-β receptor inhibitor SB431542 inhibited contact-induced expression of PTPRK. Furthermore, inhibition of Notch signaling, via knockdown of Notch1 or by γ-secretase inhibitors, significantly reduced TGF-β-induced PTPRK gene expression, indicating that Notch and TGF-β pathways function together to regulate PTPRK. Of importance, the combination of Jag1 plus TGF-β results in greater PTPRK expression and lower EGFR tyrosine phosphorylation than either ligand alone. These data indicate that Notch and TGF-β act in concert to stimulate induction of PTPRK, which suppresses EGFR activation in human keratinocytes.

Abstract 5285: Protein phosphatases modulate kinase signaling mediated Wnt activation

Abstract Multiple growth factors, signaling through their respective kinase cascades, phosphorylate beta-catenin at specific Serine residues to cause its nuclear sequestration thereby fueling Wnt driven tumor cell proliferation. Our present work identifies a group of phosphatase genes that attenuate such growth factor mediated activation of Wnt signaling in colo-rectal cancer (CRC) cells. This proposed mechanism proposes an additional mode of regulation of Wnt activity in CRC cells. Using a lentiviral TCF-LEF reporter system, we isolated distinct SW480 (primary) and SW620 (metastatic) cell fractions based on their endogenous level of Wnt activity. Receptor Tyrosine Kinase (RTK) antibody arrays using cell lysates from these cell fractions identified that FGFR3, ALK and RET signaling pathways have a positive correlation with enhanced Wnt activity. Simultaneously qPCR arrays performed on these same cellular fractions identified a total of 10 phosphatase genes whose expression levels are significantly decreased with heightened Wnt activity, out of which 4 genes PHLPP, PHLPPL, PTPRK and PTPN6 are known to regulate the aforementioned RTK pathways. Of these phosphatase genes, PTPRK has been reported to undergo gene fusion events with RSPO3 (a non-canonical activator of Wnt) in CRC patients. Since the fusion gene product provides no additional Wnt activation that the wild-type RSPO3, we theorized that these fusion events occur either to allow CRC cells to utilize the enhanced promoter activity of the PTPRK gene promoter, or to nullify the Wnt attenuating properties of PTPRK. To test this hypothesis, we have presently cloned and identified PTPRK and RSPO3 gene promoter regions and wish to test their activity in distinct Wnt responsive cell fractions. Our work will allow a better understanding of how phosphatase genes may be involved in controlling the Wnt pathway and how their inactivation may contribute to CRC cell proliferation. Citation Format: Debasish Boral, Daotai Nie. Protein phosphatases modulate kinase signaling mediated Wnt activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5285. doi:10.1158/1538-7445.AM2014-5285

Tumor Derived Mutations of Protein Tyrosine Phosphatase Receptor Type K Affect Its Function and Alter Sensitivity to Chemotherapeutics in Glioma

Poor prognosis and resistance to therapy in malignant gliomas is mainly due to the highly dispersive nature of glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to therapy. Using mapping arrays to screen for genomic alterations in gliomas, we recently identified alterations of the protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to glioma biology as PTPRK can directly sense cell–cell contact and is a dephosphorylation regulator of tyrosine phosphorylation signaling, which is a major driving force behind tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-glioma therapeutics, such as temozolomide and tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-catenin signaling and improved the effect of conventional therapies for glioma. However, PTPRK mutations abrogated tumor suppressive effects of wild-type PTPRK and altered sensitivity of glioma cells to chemotherapy.

Abstract 2666: Receptor protein tyrosine phosphatase type kappa is a prognostic marker, essential for regulating malignant behavior of glioma cells

Abstract Malignant gliomas have a poor survival resulting from rapid growth of the tumor and extensive dispersion throughout the brain parenchyma. Discovery of tumor-specific biomarkers hold great promise in improving survival and thus call for better understanding of regulatory signals driving glioma cell migration and dispersal. Using genome-wide exploration, we have identified frequent genetic alterations at the Receptor protein tyrosine phosphatase type kappa (PTPRK) locus. These PTPRK alterations were among the top significant and very relevant to glioma biology since PTPRK is a dephosphorylation regulator of tyrosine phosphorylation (TP) signaling, a frequently altered signaling cascade in glioma as reported previously. Understanding PTPRK function will provide relevant novel insights into the molecular mechanisms underlying glioma cell growth and migration. PTPRK expression was analyzed by quantitative-RT-PCR and western blot. Mutations of PTPRK were identified by sequencing full length PTPRK transcripts from a subset of patients’ samples showing PTPRK loss of heterozygosity. Two major PTPRK variants were cloned and expressed in cells harboring altered PTPRK (U87MG cell line) to study their effect on PTPRK phosphatase activity and functionality. PTPRK locus undergoes allelic loss in glioma and contributes to cancer phenotype. It is an independent prognostic marker in glioma. Patients with altered PTPRK (23%) have shorter survival compared to those with normal PTPRK molecular status (p=0.001, Log-rank test, 14 vs. 30 months). PTPRK mRNA as well as protein levels were lower in tumor biopsies compared to non-tumor specimens. Mutational analysis revealed missense mutations in the phosphatase domain, resulting in altered PTPRK phosphatase activity, possibly due to changes in active site conformation. Further, PTPRK alterations changed expression profiles of the PTPRK protein as a result of altered post-translational processing. Reconstitution of PTPRK expression in glioma cells (U87MG cell line) harboring PTPRK deletions suppressed cell growth and migration which was alleviated by the PTPRK variants to differing extent. PTPRK knockdown via shRNA down-regulated its onco-suppressive function compared to PTPRK expressing cells. Our findings provide the first evidence of the key role of PTPRK expression in glioma and shed light on the biological consequences of mutations in the PTPRK gene which significantly alter PTPRK functionality. Biological relevance of PTPRK variants will be determined and validated on a large scale. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2666. doi:1538-7445.AM2012-2666

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.

Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase κ gene in LEC rats

The Long-Evans Cinnamon (LEC) rat has a spontaneous mutation, T helper immunodeficiency ( thid), which causes a markedly reduced CD4 + thymocyte population. Here we positionally clone the locus and identify a deletion in the gene encoding a receptor-like protein tyrosine phosphatase κ ( Ptprk) that led to complete loss of the transcript. The rat Ptprk gene exhibits 98% identity with the human and mouse counterparts and is expressed most abundantly in the CD4 −CD8 − double-negative stage. The downregulation of Ptprk in mouse immature thymocytes by RNA interference mimicked the thid phenotype. These results indicate that thid maps to the Ptprk locus and that functional Ptprk is crucial for lineage commitment or progression of CD4 + T cells. We also found that Ptprk appears to function in parallel with or downstream of Th-POK/cKrox (also known as ZBTB7B), a master regulator of T cell lineage decision.