title: Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, University of Padua, Padua, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tibaldi
authors.forename: A M
authors.initials: AM
authors.lastname: Brunati
authors.forename: F
authors.initials: F
authors.lastname: Zonta
authors.forename: F
authors.initials: F
authors.lastname: Frezzato
authors.forename: C
authors.initials: C
authors.lastname: Gattazzo
authors.forename: R
authors.initials: R
authors.lastname: Zambello
authors.forename: E
authors.initials: E
authors.lastname: Gringeri
authors.forename: G
authors.initials: G
authors.lastname: Semenzato
authors.forename: M A
authors.initials: MA
authors.lastname: Pagano
authors.forename: L
authors.initials: L
authors.lastname: Trentin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D018956:CD5 Antigens / Q000378:metabolism*; D002451:Cell Compartmentation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D018956:CD5 Antigens; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6