Proteinaceous Regulators and Inhibitors of Protein Tyrosine Phosphatases

Abstract

Proper control of the phosphotyrosine content in signal transduction proteins is essential for normal cell behavior and is lost in many pathologies. Attempts to normalize aberrant tyrosine phosphorylation levels in disease states currently involve either the application of small compounds that inhibit tyrosine kinases (TKs) or the addition of growth factors or their mimetics to boost receptor-type TK activity. Therapies that target the TK enzymatic counterparts, the multi-enzyme family of protein tyrosine phosphatases (PTPs), are still lacking despite their undisputed involvement in human diseases. Efforts to pharmacologically modulate PTP activity have been frustrated by the conserved structure of the PTP catalytic core, providing a daunting problem with respect to target specificity. Over the years, however, many different protein interaction-based regulatory mechanisms that control PTP activity have been uncovered, providing alternative possibilities to control PTPs individually. Here, we review these regulatory principles, discuss existing biologics and proteinaceous compounds that affect PTP activity, and mention future opportunities to drug PTPs via these regulatory concepts.

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…Genetically engineered mouse models have significantly contributed to our understanding of the physiological role of PP1 holoenzymes in health and diseases as they can determine in vivo gene function and identify disease-causing target genes [19,20]. Also, mouse models are often crucial for discovering therapeutic targets as demonstrated by the history of the development of PTP-targeted drugs [21,22]. The first breakthrough was the discovery of the phenotype of mice with a global deletion of protein tyrosine phosphatase PTP1B.…”

“…The first breakthrough was the discovery of the phenotype of mice with a global deletion of protein tyrosine phosphatase PTP1B. Because these mice were hypersensitive to insulin and resistant to obesity, academics and pharmaceutical companies began to search for PTP1B inhibitors to treat type 2 diabetes and obesity [21,22].…”

<p>Inhibition of microRNA-15b-5p Attenuates the Progression of Oral Squamous Cell Carcinoma via Modulating the <em>PTPN4</em>/STAT3 Axis</p>

“…PTPs control the phosphotyrosine concentration in signal transduction proteins, which is crucial for normal cell states and is linked to many pathologies once it is lost. 30 Theoretically speaking, PTPs mediate dephosphorylation of proteins, leading to termination of signaling pathways and the subsequent inhibition of cell proliferation, growth and differentiation, and either antioncogenic or oncogenic phosphatases have been found. 16 Two PTP members PTP receptor R (PTPRR) and PTP receptor-type, Z polypeptide 1 (PTPRZ1) were found as indicators for increased tumor differentiation and favorable survival rate in patients with OSCC.…”

Mapping actionable pathways and mutations in brain tumours using targeted RNA next generation sequencing

“…Examples are loss of function mutations in tumour suppressor genes (e.g. p53 and CDKN2A) and DNA repair proteins , leading to genetic instability and loss of cell cycle control) [1–3], and activating mutations, amplifications or fusion events in proto-oncogenes [4, 5]. Other shared features are related to micro-environmental effectors, such as altered metabolism as a result of hypoxia [6, 7], induction of angiogenesis [8] and immune suppression [9].…”