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.