XB130 Mediates Cancer Cell Proliferation and Survival through Multiple Signaling Events Downstream of Akt

Abstract

XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G1-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking-down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3β, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells.

XB130—A Novel Adaptor Protein: Gene, Function, and Roles in Tumorigenesis

“…By acting as an upstream regulator of PI3K, XB130 plays an important role in mediating cell survival and proliferation through Akt pathways [21] and in cell migration through Rac-dependent pathways [12, 19]. The role of XB130 is not limited to protein activity and several studies have shown that XB130 also participates in the regulation of gene expression [14] (Figure 4).…”

XB130, a New Adaptor Protein, Regulates Expression of Tumor Suppressive MicroRNAs in Cancer Cells

“…XB130 is a tyrosine kinase substrate, which can be tyrosine phosphorylated by Src and other tyrosine kinases [7]–[9], and interact with Src through its N-terminal SH2 and SH3 domain binding motifs, and mediates Src related transactivation of SRE and AP-1 [7]. The N-terminus of XB130 also contains a YxxM motif that can bind to the p85α subunit of phosphatidyl inositol 3-kinase (PI3K) through its SH2 domains, and subsequently activate Akt [2], [8].…”

“…The N-terminus of XB130 also contains a YxxM motif that can bind to the p85α subunit of phosphatidyl inositol 3-kinase (PI3K) through its SH2 domains, and subsequently activate Akt [2], [8]. XB130 mediates cell survival and proliferation through multiple signals down-stream from Akt [9]. XB130 in human thyroid cancer cells regulates tumor growth as shown in an animal model with nude mice, through promotion of cell proliferation and inhibition of apoptosis.…”

XB130: A novel adaptor protein in cancer signal transduction

“…However, XB130 was also identified in different cancer cells in the absence of RET/PTC, and subsequent to stimulating Akt, XB130 was found to regulate cancer cell cycle progression and survival through multiple Akt downstream molecules (67). For example, the cyclin-dependent kinase inhibitor p27Kip1 nuclear translocation can cause G1 arrest and the cyclin-dependent kinase inhibitor p21Cip1/WAF1 can negatively modulate cell cycle progression by inhibiting the activation of the cyclin/cdk2 complex.…”