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<p>Protein tyrosine phosphatase non-receptor type 13 (PTPN13) is a non-receptor protein tyrosine phosphatase with context-dependent roles as tumour suppressor or promoter. Its modular structure supports multiple molecular interactions, including a critical one with β-catenin, a regulator of the haematopoietic system. We previously identified three pathogenic <i>PTPN13</i> mutations in families with acute lymphoblastic leukaemia (ALL), anaemia, and/or inherited bone marrow failure (IBMF). Our current findings reveal that these mutations impair the PTPN13–β-catenin interaction. β-catenin and PTPN13 are stabilised upon B-cell receptor (BCR) activation, while PTPN13 silencing reduces Bruton’s tyrosine kinase (BTK) activation and β-catenin levels, indicating that PTPN13 modulates BCR signalling at multiple points. Together with prior evidence showing that <i>PTPN13</i> mutations compromise protein stability and decrease β-catenin levels, these data support a role for disrupted lymphoid signalling. Altered expression of key surface markers (CD25 and CD38) upon silencing of either PTPN13 or β-catenin further supports this interpretation. In conclusion, our study identifies the PTPN13–β-catenin axis as a critical regulator of lymphoid cell homeostasis and highlights its disruption as a potential driver of haematological abnormalities in patients carrying <i>PTPN13</i> mutations.</p>

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Altered PTPN13–β-catenin interaction by pathogenic mutations and involvement of this axis in B-cell receptor signalling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • David A. Cabrera-Riofrío,
  • Hongbing Li,
  • Clara García-Calvo,
  • Carmen Sánchez-Bernal,
  • Jesús Sánchez-Yagüe,
  • Yigal Dror,
  • Rubén M. Buey,
  • Ángel Hernández-Hernández

摘要

Protein tyrosine phosphatase non-receptor type 13 (PTPN13) is a non-receptor protein tyrosine phosphatase with context-dependent roles as tumour suppressor or promoter. Its modular structure supports multiple molecular interactions, including a critical one with β-catenin, a regulator of the haematopoietic system. We previously identified three pathogenic PTPN13 mutations in families with acute lymphoblastic leukaemia (ALL), anaemia, and/or inherited bone marrow failure (IBMF). Our current findings reveal that these mutations impair the PTPN13–β-catenin interaction. β-catenin and PTPN13 are stabilised upon B-cell receptor (BCR) activation, while PTPN13 silencing reduces Bruton’s tyrosine kinase (BTK) activation and β-catenin levels, indicating that PTPN13 modulates BCR signalling at multiple points. Together with prior evidence showing that PTPN13 mutations compromise protein stability and decrease β-catenin levels, these data support a role for disrupted lymphoid signalling. Altered expression of key surface markers (CD25 and CD38) upon silencing of either PTPN13 or β-catenin further supports this interpretation. In conclusion, our study identifies the PTPN13–β-catenin axis as a critical regulator of lymphoid cell homeostasis and highlights its disruption as a potential driver of haematological abnormalities in patients carrying PTPN13 mutations.