SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies

Cell Signal. 2022 Jun;94:110331. doi: 10.1016/j.cellsig.2022.110331. Epub 2022 Apr 7.

Abstract

SYK and ZAP70 nonreceptor tyrosine kinases serve essential roles in initiating B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and T-lymphocytes, respectively. Despite their structural and functional similarity, expression of SYK and ZAP70 is strictly separated during B- and T-lymphocyte development, the reason for which was not known. Aberrant co-expression of ZAP70 with SYK was first identified in B-cell chronic lymphocytic leukemia (CLL) and is considered a biomarker of aggressive disease and poor clinical outcomes. We recently found that aberrant ZAP70 co-expression not only functions as an oncogenic driver in CLL but also in various other B-cell malignancies, including acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma. Thereby, aberrantly expressed ZAP70 redirects SYK and BCR-downstream signaling from NFAT towards activation of the PI3K-pathway. In the sole presence of SYK, pathological BCR-signaling in autoreactive or premalignant cells induces NFAT-activation and NFAT-dependent anergy and negative selection. In contrast, negative selection of pathological B-cells is subverted when ZAP70 diverts SYK from activation of NFAT towards tonic PI3K-signaling, which promotes survival instead of cell death. We discuss here how both B-cell malignancies and autoimmune diseases frequently evolve to harness this mechanism, highlighting the importance of developmental separation of the two kinases as an essential safeguard.

Keywords: Antigen receptor signaling; B-cell malignancies; Negative selection; SYK; ZAP70.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autoimmune Diseases*
  • Autoimmunity
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Antigen, B-Cell
  • Syk Kinase
  • ZAP-70 Protein-Tyrosine Kinase

Substances

  • Receptors, Antigen, B-Cell
  • SYK protein, human
  • Syk Kinase
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human