Lyn Expression in Osteoblastic Osteosarcoma Tissues and Its Correlation with Clinicopathologic Factors

BACKGROUND: The Src family kinases (SFKs) are involved in multiple aspects of tumorigenesis, such as, proliferation, migration, and angiogenesis, and are involved in the generation and progression of many types of tumors. Furthermore, dasatinib, a general SFKs inhibitor was recently approved for use in chronic myeloid leukemia. This study was performed to evaluate the expression of Lyn, a member of the SFKs, in osteosarcoma tissues. METHODS: One hundred and sixteen patients with osteoblastic osteosarcoma were selected for Lyn expression analysis. The correlation between Lyn expression in tumor sections and patients' clinicopathologic characteristics and the prognostic significance of Lyn expression were evaluated. RESULTS: Lyn was found to be expressed in 52 of the 116 patients (44.8%), and Lyn positive tumor was found to be significantly associated with a lytic tumor pattern on plain radiographs (p = 0.04). Furthermore, those positive for Lyn showed longer metastasis free survival (5-year metastasis free survival, 65.2% for Lyn positive and 46.8% for Lyn negative; p = 0.06), though this was only marginally significant. CONCLUSIONS: Lyn was found to be overexpressed in osteosarcoma tissues, and this overexpression was found to be correlated with osteolysis.

Multi-transmembrane protein K15 of Kaposi's sarcoma-associated herpesvirus targets Lyn kinase in the membrane raft and induces NFAT/AP1 activities

Viral proteins of gamma-2 herpesviruses, such as LMP2A of Epstein Barr virus (EBV) and Tip of herpesvirus saimiri (HVS) dysregulate lymphocyte signaling by interacting with Src family kinases. K15 open reading frame of Kaposi's sarcoma associated herpesvirus (KSHV), located at the right end of the viral genome, encodes several splicing variants differing in numbers of transmembrane domains. Previously, we demonstrated that the cytoplasmic tail of the K15 protein interfered with B cell receptor signal transduction to cellular tyrosine phosphorylation and calcium mobilization. However, the detailed mechanism underlying this phenomenon was not understood. In the C-terminal cytoplasmic region of K15, putative binding domains for Src-SH2 and -SH3 were identified. In this study, we attempted to characterize these modular elements and cellular binding protein(s) by GST pull down and co-immunoprecipitation assays. These studies revealed that K15 interacted with the major B cell tyrosine kinase Lyn. In vitro kinase and transient co-expression assays showed that the expression of K15 protein resulted in activation of Lyn kinase activity. In addition, GST pull down assay suggested that the SH2 domain of Lyn alone was necessary for interaction with the C-terminal SH2B (YEEV) of K15, but the addition of Lyn SH3 to the SH2 domain increases the binding affinity to K15 protein. The data from luciferase assays indicate that K15 expression in BJAB cells induced NFAT and AP1 activities. The tyrosine residue in the C-terminal end of K15 required for the Lyn interaction appeared to be essential for NFAT/AP1 activation, highlighting the significance of the C-terminal SH2B of K15 as a modular element in interfering with B lymphocyte signaling through interaction with Lyn kinase.