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.
Highlights
XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis [1]
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
These results indicate that XB130 plays important roles in the regulation of cancer cell proliferation either in the presence or the absence of RET/PTC
Summary
XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis [1]. Human xb130 gene was discovered during the cloning process of human afap gene [2,3,4]. It encodes 818 amino acids with an apparent molecular size of approximately 130 kDa. The overall structure of XB130 shares similarity with AFAP is known as AFAP1 like protein 2 (AFAP1L2). The Nterminal region of XB130 includes several tyrosine phosphorylation sites and proline-rich sequence, which can potentially interact with SH2 and SH3 domain-containing proteins, respectively. Silencing endogenous XB130 can cause a decrease in the rate of wound closure, inhibit matrigel invasion, and reduce lamellipodial persistence and cell spreading, which suggest that it plays an important role in cell motility and invasion [5]
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