Roles of XB130, a novel adaptor protein, in cancer

Abstract

Adaptor proteins, with multi-modular structures, can participate in the regulation of various cellular functions. During molecular cloning process of actin filament associated protein, we have discovered a novel adaptor protein, referred to as XB130. The human xb130 gene is localized on chromosome 10q25.3, and encodes an 818 amino acid protein. The N-terminal region of XB130 includes several tyrosine phosphorylation sites and a proline-rich sequence that might interact with Src homology 2 and 3 domain-containing proteins, respectively. Our studies have indeed implicated XB130 as a likely substrate and regulator of tyrosine kinase-mediated signaling. Down-regulation of endogenous XB130 with small interfering RNA reduced c-Src activity, IL-8 production and phosphorylation of Akt in human lung epithelial cells. Further, XB130 binds the p85α subunit of phosphatidyl-inositol-3-kinase and subsequently mediates signaling through RET/PTC in thyroid cancer cells. Knockdown of XB130 using small interfering RNA inhibited G ₁-S phase progression, induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death in human lung and thyroid cancer cells. Growth of tumors in nude mice formed from XB130 short hairpin RNA stably transfected human thyroid cancer cells were significantly reduced, with decreased cell proliferation and increased apoptosis. Further, XB130 has a high affinity to lamellipodial F-actin meshwork and is involved in the motility and invasiveness of cancer cells. Gene expression profiling identified 246 genes significantly changed in XB130 short hairpin RNA transfected thyroid cancer cells. Among them, 57 genes are related to cell proliferation or survival, including many transcription regulators. Pathway analysis showed that the top ranked disease related to XB130 is Cancer, and the top molecular and cellular functions are Cellular Growth and Proliferation, and Cell Cycle. These observations suggest that the expression of XB130 may affect cell proliferation, survival, motility and invasion in various cancer cells. A deeper understanding of these mechanisms may lead to the discovery of XB130 as an important mediator in tumor development and as a novel therapeutic target for cancer.