Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells

Leukemia. 2011 Nov;25(11):1768-81. doi: 10.1038/leu.2011.152. Epub 2011 Jun 24.


In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B-CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain-containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies in B-CLL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis*
  • Blotting, Western
  • CD5 Antigens / metabolism*
  • Cell Compartmentation
  • Female
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Male
  • Middle Aged
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Subcellular Fractions / metabolism
  • src Homology Domains
  • src-Family Kinases / physiology*


  • CD5 Antigens
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6