A Splice Variant of CD99 Increases Motility and MMP-9 Expression of Human Breast Cancer Cells through the AKT-, ERK-, and JNK-dependent AP-1 Activation Signaling Pathways

Abstract

CD99, a cell surface glycoprotein with a molecular mass of 32 kDa, was originally described as a human thymus leukemia antigen (1), a Ewing sarcoma-specific membrane marker molecule (2, 3), and a putative adhesion molecule (termed E2) involved in spontaneous rosette formation of T cells with erythrocytes (4 -7). CD99 is broadly distributed on many cell types, with particularly strong expression on human cortical thymocytes, Ewing sarcoma cells, and peripheral primitive neuroectodermal tumors (3,8). The functional role of CD99 is not fully understood, and most information about its functions is derived from triggering CD99-mediated signaling events with agonistic CD99 monoclonal antibodies (mAbs) 2 in hematopoietic cells. In normal cells, CD99 has been functionally implicated in cell adhesion, migration, apoptosis, differentiation, activation, and proliferation of lymphocytes and monocyte extravasation and transport of several transmembrane proteins (9 -19). In particular, the role of CD99 in the modulation of cell adhesion has been demonstrated by the ability of anti-CD99 mAbs to induce homotypic aggregation of CD4 ϩ CD8 ϩ thymocytes, whereas other anti-CD99 antibodies block spontaneous T cell-erythrocyte rosette formation (4,6,11,20). It was also shown that antibody ligation of CD99 molecules up-regulated the expression of LFA-1 (␣ L ␤ 2 integrin), and CD99-induced cell aggregation was blocked by the addition of mAbs to LFA-1 or intracellular adhesion molecule 1 (ICAM-1) in a B cell line (20). These results suggest that signal transduction via CD99 modulates cell adhesion of lymphocytes by regulating the expression level of the cell adhesion molecule, integrin LFA-1. Several signal transducing molecules, including MAPKs and protein kinase C, have been found to mediate CD99-dependent cell adhesion of T cells (21,22). In addition, it was found that CD99 on one cell binds to another neighboring CD99 on the next, indicating that CD99 is a homophilic cell surface interacting protein (18). However, the molecular mechanisms of CD99-mediated signal transduction remain largely unknown.

CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis

“…Previous studies showed that CD99 was capable of eliciting modulation of several intracellular pathways, including PI3K/Akt and RAS/MAPK (64,65) We found that CD99 knockdown inhibited Akt while increasing ERK1/2 phosphorylation. The effects on PI3K/ Akt may explain the blockade of CD99-silenced cells in G 2 /M cell cycle phase and their increased expression of the growth inhibitors p21 and/or p27, since this pathway has been shown to be required for G 2 /M phase progression and to play a key role in the stabilization of p21 and p27 (45).…”

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

“…A very recent paper also invoked c-Src functional involvement for CD99 intracellular signalling in breast cancer (Byun et al, 2006). However, the authors focused on downstream mediators activated by CD99 engagement; therefore, our study provides complementary rather than coincidental information on the role of this so far neglected molecule in tumour biology.…”

“…Indeed, the expression of the truncated isoform of CD99 appears to favour cancer malignancy by increasing anchorage-independence growth, resistance to anoikis and metastasis. The favouring role of the splice variant of CD99 in malignancy has been very recently extended also to breast cancer cells (Byun et al, 2006), indicating a more common role for this molecule than it was thought. Owing to a quite restrict pattern of expression, CD99 has been limitedly studied.…”

Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo

“…Both basal breast cancer cell lines such as MDA-MB 231 and luminal cell lines such as MCF-7 were shown to secrete MMP9 in response to ERK1/2, which suggests that the interplay between ERK1/2 and MMP9 is not limited to T4-2 cells (Liu et al 2002;Tsai et al 2003;Byun et al 2006;Zhang et al 2006). The many roles of ERK1/2 activation in promoting cell proliferation have been studied widely.…”