Protein Tyrosine Phosphatase Receptor Type γ Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia

Members of the Protein Tyrosine Phosphatase (PTPs) family are associated with growth regulation and cancer development. Acting as natural counterpart of tyrosine kinases (TKs), mainly involved in crucial signaling pathways such as regulation of cell cycle, proliferation, invasion and angiogenesis, they represent key parts of complex physiological homeostatic mechanisms. Protein tyrosine phosphatase gamma (PTPRG) is classified as a R5 of the receptor type (RPTPs) subfamily and is broadly expressed in various isoforms in different tissues. PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region frequently subject to loss of heterozygosity in various tumors. However, reported mechanisms of PTPRG downregulation include missense mutations, ncRNA gene regulation and epigenetic silencing by hypermethylation of CpG sites on promoter region causing loss of function of the gene product. Inactive forms or total loss of PTPRG protein have been described in sporadic and Lynch syndrome colorectal cancer, nasopharyngeal carcinoma, ovarian, breast, and lung cancers, gastric cancer or diseases affecting the hematopoietic compartment as Lymphoma and Leukemia. Noteworthy, in Central Nervous System (CNS) PTPRZ/PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role also in this tissue. In this review, we will summarize the current knowledge on the role of PTPRG in various human cancers.

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A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

Journal of Hematology & Oncology ◽

10.1186/s13045-017-0494-z ◽

2017 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Marzia Vezzalini ◽

Andrea Mafficini ◽

Luisa Tomasello ◽

Erika Lorenzetto ◽

Elisabetta Moratti ◽

...

Keyword(s):

Monoclonal Antibody ◽

Chronic Myeloid Leukemia ◽

Protein Tyrosine Phosphatase ◽

Myeloid Leukemia ◽

Tyrosine Phosphatase ◽

Receptor Type ◽

Protein Tyrosine

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Regulative Loop between β-catenin and Protein Tyrosine Receptor Type γ in Chronic Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms21072298 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2298 ◽

Cited By ~ 1

Author(s):

Luisa Tomasello ◽

Marzia Vezzalini ◽

Christian Boni ◽

Massimiliano Bonifacio ◽

Luigi Scaffidi ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tyrosine Phosphatase ◽

Promoter Hypermethylation ◽

Suppressor Gene ◽

Receptor Type ◽

Methyl Transferase ◽

Protein Tyrosine ◽

Over Expression ◽

First Time

Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene, down-regulated in Chronic Myeloid Leukemia (CML) cells by the hypermethylation of its promoter region. β-catenin (CTNNB1) is a critical regulator of Leukemic Stem Cells (LSC) maintenance and CML proliferation. This study aims to demonstrate the antagonistic regulation between β-catenin and PTPRG in CML cells. The specific inhibition of PTPRG increases the activation state of BCR-ABL1 and modulates the expression of the BCR-ABL1- downstream gene β-Catenin. PTPRG was found to be capable of dephosphorylating β-catenin, eventually causing its cytosolic destabilization and degradation in cells expressing PTPRG. Furthermore, we demonstrated that the increased expression of β-catenin in PTPRG-negative CML cell lines correlates with DNA (cytosine-5)-methyl transferase 1 (DNMT1) over-expression, which is responsible for PTPRG promoter hypermethylation, while its inhibition or down-regulation correlates with PTPRG re-expression. We finally confirmed the role of PTPRG in regulating BCR-ABL1 and β-catenin phosphorylation in primary human CML samples. We describe here, for the first time, the existence of a regulative loop occurring between PTPRG and β-catenin, whose reciprocal imbalance affects the proliferation kinetics of CML cells.

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Protein Tyrosine Phosphatase Receptor Type O (PTPRO) Exhibits Tumor Suppressor Properties in K562 Cells by Dephosphorylating Bcr-Abl.

Blood ◽

10.1182/blood.v110.11.2914.2914 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2914-2914

Author(s):

Sarmila Majumder ◽

Tasneem Motiwala ◽

Kalpana Ghoshal ◽

Huban Kutay ◽

Jharna Datta ◽

...

Keyword(s):

Tumor Suppressor ◽

Protein Tyrosine Phosphatase ◽

Cpg Island ◽

Tyrosine Phosphatase ◽

Ectopic Expression ◽

K562 Cells ◽

Myelogenous Leukemia ◽

Receptor Type ◽

Protein Tyrosine ◽

Catalytically Active

Abstract Regulation of protein phosphorylation by concerted action of protein kinases and phosphatases is important for normal physiological processes. Altered function or expression of one or more components of these regulatory molecules leads to many pathological conditions including cancer. We have previously shown that the truncated form of the receptor-type protein tyrosine phosphatase PTPROt predominantly expressed in haematopoietic cells is suppressed in Chronic Lymphocytic Leukemia (B-CLL). A direct correlation of CpG island methylation and reduced expression of the gene was observed in primary CLL samples and in several leukemia cell lines. To assess the functional significance of loss of PTPROt function in leukemia, we selected K562 cells as a model system, as PTPROt expression is silenced in these cells and is reactivated upon treatment with DNA hypomethylating agents. Ectopic expression of the catalytically active PTPROt inhibited growth of K562 cells and their clonogenic survival in soft agar (a characteristic of cancer cells). Further, cells expressing PTPROt exhibited delayed entry into S-phase from G0/G1 phase. Induction of apoptosis increased significantly in K562 cells expressing functional phosphatase upon serum withdrawal or exposure to the apoptogenic agent camptothecin. Tumorigenic potential of K562 cells in athymic nude mice was also significantly reduced upon ectopic expression of PTPROt. Finally, we demonstrate that the Bcr-Abl fusion protein, product of abnormal chromosomal translocation [t(9;22)] in chronic myelogenous leukemia, is a substrate of PTPROt. Tyrosine phosphorylation of this potent kinase was markedly reduced in K562 cells expressing the catalytically active PTPROt. Enhanced dephosphorylation of Bcr-Abl by PTPROt both in vivo and in vitro explains the observed phenotypes of the PTPROt expressing K562 cells. These data taken together delineate the molecular mechanism of tumor suppressor function of PTPROt in leukemic cells characterized by Philadelphia chromosome. (This work was supported by a grant CA101956 from the National Institutes of Health).

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