Protein Tyrosine Phosphatase Receptor Gamma: History
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Subjects: Cell Biology
Contributor:
Claudio Sorio
,
Roberta Latorre

Protein tyrosine phosphatase gamma (PTPRG) is an enzyme that remove phosphate groups from phosphotyrosine residues of specific intracellular targets. It belongs to the tyrosine phosphatase (PTP) family of proteins and it is widely expressed in human tissues. 

  • Tyrosine phosphatase
  • cell differentiation
  • diabetes
  • CNS disease
  • liver disease
  • kidney disease
  • cell adhesion
  • plasma
  • endothelium
  • leukemia

1. Introduction

Phosphorylation and dephosphorylation are important post-translational modifications that occur in the different aminoacid residues. These biological processes are essential mechanisms for intracellular signal transduction and for switching enzyme activity. The balance between the activities of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) allows them to maintain cellular homeostasis [1]. PTPs are generally divided in proteins tyrosine phosphatase (PTPs) and proteins serine-threonine phosphatase (PSTPs) based on their substrate specificity for tyrosine, serine, and threonine [2][3]. Members of the PTP family are primarily involved in signaling pathways such as cell cycle regulation, proliferation, invasion and angiogenesis, acting as a natural counterpart of tyrosine kinases (TKs). Protein tyrosine phosphatase gamma (PTPRG) belongs to R5 group of the receptor type phosphatase subfamily (RPTP), together with its homologous PTPRZ, and is widely expressed in various isoforms in different tissues [4][5]. PTPRG gene encodes for a transmembrane protein composed in the extracellular region (ECD) by the homologous α-carbonic anhydrase like domain (CAH) and the Fibronectin type III domain and in the intracellular side by two phosphatase domains. The domain D1 is the catalytically active phosphatase portion while the domain D2 is a pseudophosphatase domain lacking of enzymatic activity and probably involved in the stability, substrate specificity and binding of docking proteins [6][7][8]. Several PTPRG isoforms have been described: PTPRG-A is a full-length isoform, PTPRG-B lacks 29 amino acids in the juxtamembrane position, PTPRG-C contains only one phosphatase domain and PTPRG-D (sPTPRG) is a soluble isoform wich has lost all phosphatase activity [9]. PTPRG isoforms have important roles in various human tissues and diseases, including different types of cancer and inflammatory disorders.

2. Physiological roles of PTPRG

2.1 PTPRG Affects Cell Differentiation

PTPRG was originally identified in the central nervous system (CNS) [6], together with PTPRZ [10][11], where it plays a role in differentiation and neurogenesis. PTPRG mRNA and the different protein isoforms are expressed in neuronal and accessory cells, including sensory pyramidal cells, microglia and Purkinje cells [12][13][14]. It was reported, in a study conducted in chicken spinal cord, that PTPRG perturbation significantly reduce progenitor rates and the number of neuronal precursors, resulting in neuroepithelial hypoplasia. This reveals its potential role in the survival and localization/movement of motor neuron precursor (MNs) [12]. In this contest, PTPRG was suggested to interact with the WNT/β-catenin signaling and the modulation of β-catenin phosphorylation levels with the consequent influence of the TCF/LEF complex. Loss of function of PTPRG was associated to increase apoptosis and defective cell–cell adhesion in progenitors and precursors of MNs while gain-of-function causes suppression of Wnt/β-catenin-driven TCF signalling [15]. In murine embryonic stem cells, PTPRG was expressed in a limited timeframe, suggesting an accurate regulation of PTPs during cell differentiation. Of note, its downregulation in embryonic stem (ES) cells is associated to complete lack of hematopoietic colonies [8]. Altogether, these data suggest an important regulatory role in key processes affecting embryonal development in different cellular models and species.

2.2 Cell Adhesion

Regarding the potential role of PTPRG in cell adhesion, it is known that the growth factor pleiotropin (PTN) and contactin (CNTN1) are able to bind the extracellular domain (ECD) of the homolog PTPRZ [16] and these interactions can regulate various signals during neuronal development [17][18]. Additionally, some members of this family (CNTN3-6) may also be potential ligands for the CAH domain of PTPRG [19]. Indeed, structural and biochemical investigations have shown an interaction with CNTN3-6, in particular CNTN3, which forms complexes with PTPRG on the membranes of different rod photoreceptors of the murine retina [20]. Furthermore, the silencing of CNTN6 or PTPRG deficiency, both expressed in layer V of the cerebral cortex, alters motor coordination in mouse models during specific tests [12][21] suggesting the importance of the interaction among these partners and the role of PTPRG in the acquisition of correct motor function. A link with adhesion processes was also found in leukocytes. Integrins are a large family of heterodimeric cell surface receptors and drive cell-to-cell and cell-to-matrix adhesion and migration mechanisms [22]. In human primary monocytes, the PTPRG phosphatase activity, prevent integrin activation triggered by chemoattractants mediating rapid arrest in underflow adhesion assays. Importantly, PTPRG seems to inhibit the transition to high-affinity state of LFA-1, through JAK2 dephosphorylation [23]. The same approach was utilized in healthy B-lymphocytes compared to chronic lymphocytic leukemia cells (CLL). Activated PTPRG decreases the activity of JAK2 and BTK kinases involved in chemokine signaling to LFA-1 and VLA-4 Integrins activation [24][25].

2.3 PTPRG as HCO3- Sensor

PTPRG and PTPRZ have extracellular domains (ECDs) that are 35%–40% identical to the catalytic domains of human carbonic anhydrases (CAs), family of enzymes involved in the interconversion of HCO3- and CO2 [26]. The CAH-like domain of PTPRG-ECD lacks key histidine residues essential for catalytic activity [6], suggesting a non-catalytic role of this domain. A possible role in the regulation of acid–base balance was described in renal proximal tubules (PTs) in PTPRG –/– mice, emphasizing the loss of ability to counteract the basolateral [HCO3-] changes, compared to WT. In addition, in a simulated metabolic acidosis PTPRG interferes with the restoration of the arteriolar pH compared to WT, showing a substantial acidosis in PTPRG –/– mice [27]. In supporting the involvement of PTPRG as CO2/ HCO3- sensor, the same role was also confirmed at the arteriolar level in PTPRG –/– mice. Lastly, Ptprg was suggested to exert HCO3- sensor function and to regulate the endothelium-dependent vasorelaxant effects. In particular, it has demonstrated that endothelial Ptprg affects the vasomotor effects induced by CO2/HCO3- by regulating the Ca2+ sensitivity in arteriolar VSMC (vascular smooth muscle cells) that might enhances intracellular [Ca2+ ] in endothelial cells by implementing NO synthesis and endothelium-dependent hyperpolarization (EDH)-type responses [28][29].

3. PTPRG in disease

3.1. Cancers

PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region subjected to genetic and epigenetic alterations, including non-random deletions, loss of heterozygosity, and alteration of the CpG islands methylation profile in several types of cancer [30][31]. In particular, PTPRG gene shows promoter hypermethylation in cutaneous T-cell lymphoma and melanoma and it harbors point mutations and deletions region in colon, renal and lung carcinomas. Moreover, lower expression levels of PTPRG have been reported in various cancers [32][33][34]. However, a tumor suppressor role in tumors might not be ruled out. In particular, in Central Nervous System (CNS) PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role in this tissue [35].

3.2. Neuropsychiatric and behavioral disorders

In addition to the role of PTPs in the differentiation and synaptic organization of the CNS, they can take part during the modulation of the processes related to learning and memory [36][37]. Harroch’s group, using PTPRG–/– and PTPRZ–/– mice identified specific behavioral changes in the animals. The loss of combined or individual phosphatase was associated with a specific neurotransmitter modulation in distinct areas of the brain, indicating these as appealing therapeutic targets [38]. In the present case, PTPRG has a precise distribution in the brain and is characteristic of a group of neurons [12][13]. Its high affinity for contactin members, which are involved in autism spectrum disorder (ASD), indicate a potential role in this disease [39][40]. Several evidence suggesting PTPRG as a susceptible gene involved also in neuropsychiatric disorders. Whole-genome sequencing analysis in several cohorts of schizophrenic patients revealed mutations involving five genes, including PTPRG. Likewise, PTPRG has been associated with Alzheimer’s disease (AD), one of the most frequent forms of dementia in the world [41]. The predominant form of Alzheimer’s diagnosed is late onset (LOAD), in which the strongest risk factor considered remains APOE-"4. A single-nucleotide polymorphism (SNP) was identified on PTPRG; the rs7609954 variant achieves high genome-wide significance pointing to PTPRG and its phosphatase regulatory functions as a possible risk gene for late-onset forms of Alzheimer's disease [42].

3.3. Inflammation

The study of PTPRG in the CNS of rat brain unearthed different PTPRG isoforms derived from alternative splicing. Higher expression of the soluble protein form (sPTPRG) was found during the embryonic stages [43]. In mice treated with LPS for 24 h, a general inflammatory state was induced and was associated with increased expression of all PTPRG isoforms in cortical astrocytes, particularly the 120 KDa soluble isoform. In 5XFAD Alzheimer’s disease mouse model, astrocytes surrounding the -amyloid plaques are highly positive for PTPRG expression, suggesting as a possible factor for astrocytic activation during neuroinflammation [13]. Furthermore, this processed isoform (sPTPRG) has been shown to be present in both human and murine liver and serum. These data led to the analysis of primary serum samples from healthy donors and patients with elevated alanine aminotransferase (ALT), an established biomarker of liver injury [44]. High serum ALT levels correlate with increased levels of soluble PTPRG compared to healthy donor samples, suggesting PTPRG as a putative biomarker of liver injury [45]. Potential role as disease biomarker is suggested by the analysis of cerebrospinal fluid (CSF) that identified the closely related  sPTPRZ as a biomarker of brain tumors [46]. PTPRG involvement in metabolic disorders was also supported by several published data. Chronic inflammatory processes are often found in overweight or obese individuals, where complications such as insulin resistance, type 2 diabetes (T2DM), liver and cardiovascular disease and cancer may occur [47][48]. In this context a role of phosphatases as insulin receptor (IR) inactivators was proposed [49]. In particular Bottini’s group identified small-molecule inhibitor of LMWPTP (low-molecular-weight tyrosine phosphatase) capable of blocking insulin resistance and T2DM occurrence [50]. In humans liver PTPRG overexpression appears to correlate with inflammatory mechanisms and obesity [51]. Molecular mechanisms analysis performed on PTPRG–/– mice showed a robust improvement in glucose metabolism induced by the increased insulin sensitivity in hepatocytes, thus remaining protected from the development of hyperglycemia when compared to PTPRG+/+. Hepatic insulin resistance was found in Ptprg-overexpressing mice at values comparable to obese subjects. Interestingly inflammatory states such as obesity are able to generate an NF-kB-induced PTPRG expression mechanism due to a kB-binding site identified on the PTPRG promoter [51].

3.4. Other Diseases

Several PTPRG roles are yet to be confirmed, but some recent evidence has linked this phosphatase with renal and corneal dysfunctions. Acute kidney injury (AKI) is a kidney disorder characterized by a heterogeneous group of dysfunctions such as decreased glomerular filtration rate with and oliguria with a variable etiology [52]. The study of biomarkers such as miRNAs in the various stages of AKI suggested a possible prediction profile of recovering/non-recovering patients after 90 days. A screening on different miRNAs in AKI patients has reported the upregulation of miR-141, which both in a model of H2O2-induced tissue damage or in samples disease is able to negatively modulate PTPRG mRNA expression. The downregulation of PTPRG could therefore be fundamental for the acceleration of renal fibrotic processes through EGFR hyper-stimulation, formerly known as PTPRG substrate [53]. Degenerative disease named Fuchs’ endothelial dystrophy (FED) can affect the corneal endothelium, generating microscopic outgrowths (guttae) in the corresponding basal lamina. Although a strong correlation with the disease was found for some genes (TCF4, TCF8, AGBL1, LOXHD1, SLC4A11, and others), the study of PTPRG on several SNPs (rs7640737 and rs10490775) appear conflicting, showing an association without reaching a genome-wide significance in FED [54][55][56][57].

 

Figure 1. Summary of the role of PTPRG in physiopathology of non-neoplastic cell

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