Biochemical, Enzymatic, and Computational Characterization of Recurrent Somatic Mutations of the Human Protein Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma

Abstract

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma.

Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway

“…Protein tyrosine kinases and PTPs are the main regulators of protein tyrosine phosphorylation and dephosphorylation [ 54 ]. PTP1B is a negative regulator of insulin receptors and is ubiquitously expressed in various metabolic tissues, particularly the liver, skeletal muscle, and adipose tissues [ 55 ]. In recent years, PTP1B has attracted considerable attention as a potential therapeutic target in metabolic syndromes [ 56 , 57 , 58 ].…”

Molecular Aspects of Hematological Malignancies and Benign Hematological Disorders

“…Many of its molecular drivers, however, remain evasive despite significant advances that have been carried out in the management of blood cancers. An in vitro investigation carried out by Liu et al, was able to generate a complex characterization of the V184D, R221G, and G259V human protein tyrosine phosphatase 1B mutants, revealing a potential role of this enzyme in lymphomagenesis [ 9 ].…”