title: PAK1 tyrosine phosphorylation is required to induce epithelial-mesenchymal transition and radioresistance in lung cancer cells.
abstract: The p21-activated Ser/Thr kinase 1 (PAK1) kinase has an essential role in tumorigenesis and cell survival in many cancers, but its regulation is not fully understood. In this study, we showed that in response to irradiation of lung cancer cells, PAK1 was upregulated, tyrosine phosphorylated, and translocated to the nucleus. Tyrosine phosphorylation relied upon JAK2 kinase activity and was essential for PAK1 protein stability and binding to Snail. This radiation-induced JAK2-PAK1-Snail signaling pathway increased epithelial-mesenchymal transition (EMT) by regulating epithelial and mesenchymal cell markers. Notably, JAK2 inhibitors mediated radiosensitization and EMT blockade in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that JAK2 phosphorylates and stabilizes functions of PAK1 that promote EMT and radioresistance in lung cancer cells, with additional implications for the use of JAK2 inhibitors as radiosensitizers in lung cancer treatment.
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
authors.forename: EunGi
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan, South Korea. Nuclear Science Research Institute, Pusan National University, Busan, South Korea.
authors.forename: HyeSook
authors.initials: H
authors.lastname: Youn
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
authors.forename: TaeWoo
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
authors.forename: Beomseok
authors.initials: B
authors.lastname: Son
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
authors.forename: JiHoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Department of Planning & Research for Radiological Emergency, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan, South Korea. Nuclear Science Research Institute, Pusan National University, Busan, South Korea.
authors.forename: Wanyeon
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Integrated Biological Science, Pusan National University, Busan, South Korea. Department of Biological Sciences, Pusan National University, Busan, South Korea. Nuclear Science Research Institute, Pusan National University, Busan, South Korea. bhyoun72@pusan.ac.kr.
authors.forename: BuHyun
authors.initials: B
authors.lastname: Youn
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D010766:Phosphorylation; D011836:Radiation Tolerance; D014443:Tyrosine / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D014443:Tyrosine; C515903:PAK1 protein, human; D054462:p21-Activated Kinases