Regulation of poly -c -RNA binding protein 1 functions by Pak1 signaling
Deregulated gene expression as a consequence of alterations in genetic and epigenetic architectures of eukaryotic cells is the main force driving tumorigenesis. Aberrant activities of tumor suppressors and oncogenic proteins result in tumor formation, and they do so by changing or affecting gene expression of target cells. Human p21-activated kinases (Paks) have been found to be important regulators of tumorigenesis and cancer cell invasiveness through modifying diverse cellular processes, including cytoskeletal remodeling and cell motility. Recently, it is suggested that Pak1 has roles in promoting cell proliferation and affecting cell cycle. However, the direct involvement of Pak1 in regulating eukaryotic gene expression, the process that is absolutely required in mediating proliferation and cell cycle, has not been well studied. In the present research, we set out to search for novel downstream Pak1 effectors which can regulate gene expression. Among other proteins, we identified a novel binding partner and substrate, poly-c binding protein 1 (PCBP1), for Pak1 We found that by specific phosphorylating PCBP1 on Thr60 and Thr127 in response to mitogenic signals, Pak1 can affect multiple steps of cellular gene expression. Upon phosphorylation by pak1, PCBP1 is then released from differentiation control element (DICE) containing mRNA which leads to activation of otherwise repressed translation of the mRNA. We also found that Pak1 signaling is required for nuclear localization of PCBP1. In the nucleus, PCBP1 is recruited to eIF4E promoter and transactivates eIF4E, an essential translation initiation factor. Moreover, we showed that Pak1-PCBP1 signaling nodule can affect CD44 v4 and v5 exon based minigene alternative splicing and that the alternative splicing functions of PCBP1 were in turn mediated by its intrinsic interaction with Caper α, a coactivator previously reported to be important for RNA splicing. Finally, we found that phosphorylation of PCBP1 by Pak1 promotes cell proliferation and enhances anchorage independent growth of cancer cells. Collectively, this study discovered a novel Pak1-PCBP1 signaling pathway that can modify multiple steps of gene expression and deregulated activities of this pathway might be responsible for Pak1 mediated tumorigenesis.
Meng, Qingchang, "Regulation of poly -c -RNA binding protein 1 functions by Pak1 signaling" (2007). Texas Medical Center Dissertations (via ProQuest). AAI3256555.