UNASSIGNED: Protein tyrosine phosphatases (PTPs), essential and evolutionarily highly conserved enzymes, govern cellular functions by modulating tyrosine phosphorylation, a pivotal post-translational modification for signal transduction. The recent strides in phosphatase drug discovery, leading to the identification of selective modulators for enzymes, restoring interest in the therapeutic targeting of protein phosphatases.
UNASSIGNED: The compilation of patents up to the year 2023 focuses on the efficacy of various classes of Tyrosine phosphatases and their inhibitors, detailing their chemical structure and biochemical characteristics. These findings have broad implications, as they can be applied to treating diverse conditions like cancer, diabetes, autoimmune disorders, and neurological diseases. The search for scientific articles and patent literature was conducted using well known different platforms to gather information up to 2023.
UNASSIGNED: The latest improvements in protein tyrosine phosphatase (PTP) research include the discovery of new inhibitors targeting specific PTP enzymes, with a focus on developing allosteric site covalent inhibitors for enhanced efficacy and specificity. These advancements have not only opened up new possibilities for therapeutic interventions in various disease conditions but also hold the potential for innovative treatments. PTPs offer promising avenues for drug discovery efforts and innovative treatments across a spectrum of health conditions.

BACKGROUND: Tetrahydrobiopterin (BH4) deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare disorder that is one of the major causes of hyperphenylalaninemia in Taiwan.
METHODS: In this study, we reviewed the clinical courses of 12 adolescent and adult patients (7 females and 5 males) with PTPS deficiency.
RESULTS: The patients were treated shortly after diagnosis through newborn screening with a combination of BH4, levodopa/carbidopa, and 5-OH-tryptophan. Their plasma phenylalanine and tyrosine levels were well controlled, and their prolactin levels were also decreased after treatment. However, their prolactin levels gradually rose as they grew into puberty, and at a current age of 27.5 [interquartile range (IQR 7.9)] years, five of the 12 patients had either highly elevated prolactin levels (> 100 ng/mL in one male patient, normal reference values, male < 11 ng/mL, female < 17 ng/mL) or symptoms, including irregular menstruation, amenorrhea, and breast swelling (in four female patients). The dosage of levodopa in these five patients (14.3 (IQR 3.0) mg/kg/day) was slightly higher than that in the other patients (p = 0.05). Magnetic resonance imaging studies did not reveal an increase in the size of the anterior pituitary gland, although a Rathke cleft cyst was found in one patient. Two patients received cabergoline treatment, which promptly lowered prolactin levels and relieved symptoms.
CONCLUSIONS: Hyperprolactinemia is common in female patients with PTPS deficiency, especially after puberty. A long-acting dopamine agonist, such as cabergoline, may be a necessary adjunctive treatment for most patients with BH4 deficiency.

Analyzing intracellular peptides generated by proteasomes is highly informative to understand the spatiotemporal regulation of protein homeostasis. A large portion of eukaryotic proteins is proteolyzed within the 20S core particle of the 26S holoenzyme, where proteins are cleaved into peptides of varying lengths. A small percentage of these peptides are presented to the immune system as a representation of the proteome content of the cell. Therefore, understanding the rules that govern proteolytic specificity and product diversity is of relevance not only to biochemistry and proteostasis but also to physiology and immunology. One of the greatest challenges is to separate such proteasome-generated peptides from the total intracellular peptidome due to the susceptibility of short unstructured peptides to myriad proteases and peptidases that are activated upon cell lysis. Here, we describe a simple and rapid method to isolate peptides that are closely associated with proteasomes or trapped inside the core particle of proteasomes in eukaryotic cells. This approach termed PTPs, for proteasome-trapped peptides, requires a limited number of cells as starting materials compared to other published methods yet still provides sufficient yields for mass spectrometry-based proteomic analysis. A single sample obtained from cultured mammalian cells allowed the identification of 1000-2000 different PTPs following LC-MS analysis with high-resolution mass spectrometer.

Umbilicaria esculenta (UE), an edible lichen, is widespread in northeast Asian countries, including China, Japan, and Korea. In the present study, we examined the antiwrinkle activity of UE. We observed that the UE extract (UEE) suppressed ultraviolet (UV)-induced matrix metalloprotein-1 (MMP-1) expression and reactive oxygen species (ROS) generation in a human keratinocyte cell line (HaCaT) and human skin tissue. In addition, UEE reversed the UV-induced decrease in collagen in the human skin tissue. Excessive and chronic UV exposure is a key factor underlying skin wrinkle formation via MMP-1 expression. As treatment with UEE disrupted the UV-activated mitogen-activated protein kinase (MAPK) signaling pathway, we applied an antibody array to unveil the underlying mechanism of UEE. Interestingly, UEE treatment inhibited ErbB2 phosphorylation, but not epidermal growth factor receptor phosphorylation, a heterodimerization partner with ErbB2. Furthermore, UEE treatment enhanced UV-suppressed phosphatase activity via ROS suppression. Collectively, our findings indicate that UEE enhances ErbB2 dephosphorylation to suppress UV-induced MMP-1 expression.

The two constitutional isomers of naphthyl phosphate have different steric properties, analogous to those of phosphotyrosine versus phosphoserine/threonine within a peptide or protein. The ratios of their respective rates of hydrolysis, assayed by measuring rates of inorganic phosphate release, have been used to probe the steric requirements around the active sites of many phosphatases in the literature. We report an NMR-based competitive method that is simpler to execute and has other advantages. It directly yields the ratio of catalytic efficiencies (V/K) of the two substrates, a more biologically relevant comparison than the ratio of initial rates (vo) or maximal rates (Vmax). The competitive method ensures that temperature, pH, enzyme and substrate concentrations, and the presence of any potential inhibitors are identical and will not skew the results. The method can be easily applied at any chosen temperature or pH, and to mutants, or under any other condition that might influence protein conformation and, thus, substrate specificity. It provides a facile screening method to select conditions for a detailed phosphopeptide screen to provide deeper insight into substrate preference.

Protein tyrosine phosphatase receptor-type Q (PTPRQ), a member of the type III tyrosine phosphatase receptor (R3 PTPR) family, is composed of three domains, including 18 extracellular fibronectin type III (FN3) repeats, a transmembrane helix, and a cytoplasmic phosphotyrosine phosphatase (PTP) domain. PTPRQ was initially identified as a transcript upregulated in glomerular mesangial cells in a rat model of glomerulonephritis. Subsequently, studies found that PTPRQ has phosphotyrosine phosphatase and phosphatidylinositol phosphatase activities and can regulate cell proliferation, apoptosis, differentiation, and survival. Further in vivo studies showed that PTPRQ is necessary for the maturation of cochlear hair bundles and is considered a potential gene for deafness. In the recent two decades, 21 mutations in PTPRQ have been linked to autosomal recessive hearing loss (DFNB84) and autosomal dominant hearing loss (DFNA73). Recent mutations, deletions, and amplifications of PTPRQ have been observed in many types of cancers, which indicate that PTPRQ might play an essential role in the development of many cancers. In this review, we briefly describe PTPRQ structure and enzyme activity and focus on the correlation between PTPRQ and human disease. A profound understanding of PTPRQ could be helpful in the identification of new therapeutic targets to treat associated diseases.

OBJECTIVE: Neuropathic, chronic pain is a common and severe complication following thoracic surgery, known as post-thoracotomy pain syndrome (PTPS). Here we evaluated the efficacy of an ultrasound-guided serratus anterior plane block (SAPB) on pain control compared to traditional pain management with intravenous opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) six months after thoracic surgery.
METHODS: In this retrospective observational study, we analyzed data from a questionnaire survey. We interviewed all patients who underwent elective video-assisted thoracoscopy surgery (VATS) at Soroka University Medical Center between December 2016 and January 2018. The responses of ninety-one patients were included.
RESULTS: Participants reported PTPS in both groups, 43% of patients in the SAPB group and 57% of patients in the standard group, which failed to reach significance. However, we demonstrated that the percentage of pain occurrence trended lower in the SAPB group. There was significantly less burning/stitching or shooting, shocking, pressure-like, and aching pain in SAPB patients compared to the standard protocol group. Patients in the SAPB group had significantly less pain located in the upper and lower posterior thorax anatomical regions compared to the standard protocol group. Moreover, we found a significant difference in occurrence of PTPS depending on the type of thoracic surgery. From both study groups, 69% of patients who underwent lobectomy reported pain, compared with 41.9% of those in the segmental (wedge resection) procedure, and 42.1% of patients in other procedures.
CONCLUSIONS: While the present study did not demonstrate a statistically significant reduction of PTPS after SAPB concerning postoperative pain control, there was a trend of a decrease. We also found significance in the type of pain and location of pain after thoracic surgery between the two groups, as well as a significant difference between pain occurrence in types of thoracic surgeries from both groups.

Receptor tyrosine kinases (RTKs) are membrane receptors that regulate many fundamental cellular processes. A tight regulation of RTK signaling is fundamental for development and survival, and an altered signaling by RTKs can cause cancer. RTKs are localized at the plasma membrane (PM) and the major regulatory mechanism of signaling of RTKs is their endocytosis and degradation. In fact, RTKs at the cell surface bind ligands with their extracellular domain, become active, and are rapidly internalized where the temporal extent of signaling, attenuation, and downregulation are modulated. However, other mechanisms of signal attenuation and termination are known. Indeed, inhibition of RTKs\' activity may occur through the modulation of the phosphorylation state of RTKs and the interaction with specific proteins, whereas antagonist ligands can inhibit the biological responses mediated by the receptor. Another mechanism concerns the expression of endogenous inactive receptor variants that are deficient in RTK activity and take part to inactive heterodimers or hetero-oligomers. The downregulation of RTK signals is fundamental for several cellular functions and the homeostasis of the cell. Here, we will review the mechanisms of signal attenuation and termination of RTKs, focusing on FGFRs.

Cancer patients who require surgery often experience peri-operative symptoms, including nausea, anxiety, and pain, which can significantly impair quality of life. Here, we review the evidence for using integrative approaches to manage these peri-operative symptoms.
Conventional peri-operative pharmacologic interventions, such as opiates for pain control, can lead to adverse effects such as respiratory depression, prolonged hospital course, and long-term dependence. Integrative medicine, also known as complementary and alternative medicine (CAM), has been explored as way to reduce peri-operative symptoms. Acupuncture, guided imagery, and loving-kindness meditation have all shown potential efficacy in reducing both peri-operative pain and anxiety in retrospective studies and small randomized controlled trials. Integrative medicine techniques, such as acupuncture, are a promising approach to control peri-operative symptoms without the associated adverse effects of more conventional pharmacologic interventions.

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers.
METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database.
RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages.
CONCLUSIONS: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.