Metastasis-suppressor KAI1/CD82 induces homotypic aggregation of human prostate cancer cells through Src-dependent pathway

Abstract

To investigate the functional role of KAI1/CD82, a metastasis suppressor for human prostate cancer, in the regulation of homotypic cell adhesion, we transfected KAI1 cDNA into DU 145 human prostate cancer cells and established stable transfectant clones with high KAI1/CD82 expression. The KAI1 transfectant cells exhibited significantly increased homotypic cell aggregation in comparison with the control transfectant cells. This aggregation of the KAI1 transfectants was further enhanced upon exposure to anti-CD82 antibody, suggesting that KAI1/CD82 may be involved in the intracellular signaling for the cell adhesion. Among several signal pathway inhibitors tested, PP1, an inhibitor of Src family kinases, significantly suppressed homotypic aggregation of the KAI1 transfectant cells. Ligation of KAI1/CD82 with anti-CD82 antibody increased endogenous Src kinase activity of the KAI1 transfectant cells. When different types of src expression constructs were retransfected into the KAI1-transfected DU 145 cells, kinase-negative mutant src transfectant cells exhibited much lower homotypic aggregation than the mock cells transfected with an empty vector. Moreover, homotypic aggregation of the mutant src transfectant cells was not enhanced by KAI1/CD82 ligation with anti- CD82 antibody. These results suggest that Src mediates the intracellular signaling pathway of KAI1/CD82 for the induction of homotypic adhesion of human prostate cancer cells.

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…Previous studies have suggested that CD82 may act positively to activate signaling to Src and FAK (Lagaudriere-Gesbert et al, 1998;Berditchevski and Odintsova, 1999;Jee et al, 2003). In T cells, anti-CD82 antibodies were shown to activate p56lck, a member of Src kinase family; however, this was only observed in the context of costimulation of the T-cell receptor and was not observed upon cell adhesion to anti-CD82 antibodies (Lagaudriere-Gesbert et al, 1998).…”

“…In T cells, anti-CD82 antibodies were shown to activate p56lck, a member of Src kinase family; however, this was only observed in the context of costimulation of the T-cell receptor and was not observed upon cell adhesion to anti-CD82 antibodies (Lagaudriere-Gesbert et al, 1998). In CD82-transfected DU145 cells, anti-CD82 antibody enhanced Src kinase activity in cell-cell aggregates in suspension independently of integrins (Jee et al, 2003). However, these two examples do not address the same biological question; what is the role of CD82 in regulating integrin functions.…”

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

“…C-Src is largely involved in pathophysiology of osteoblasts (Marzia et al, 2000) and CD99 isoforms differently affect tumour metastasis K Scotlandi et al prostate cancer (Jee et al, 2003;Recchia et al, 2003) along with the significant role that it plays in the regulation of crucial processes implicated in the pathogenesis and progression of tumours, such as cell cycle, migration, resistance to anoikis and anchorage independence (Irby and Yeatman, 2000). Therefore, we evaluated its role as a possible mediator of CD99 functions.…”

Expression of KITENIN, a KAI1/CD82 binding protein and metastasis enhancer, in bladder cancer cell lines: Relationship to KAI1/CD82 levels and invasive behaviour

“…Within this context, KAI1/ CD82 is proposed to modulate signals controlling the interactions between cells, and between cells and their extracellular environment. Consistent with this function, and a role as a metastasis suppressor, the loss of KAI1/CD82 protein expression is associated with dramatically increased in vitro invasive and in vivo metastatic behaviour of tumour cells (4)(5)(6)(7). Although it is clear that these effects are associated with reduced interactions between cells, and altered interactions between cells and specific extra-cellular matrix components, the underlying basis for these changes is unknown.…”