Author:
Fu Jie,Ling Jianhua,Li Ching-Fei,Tsai Chi-Lin,Yin Wenjuan,Hou Junwei,Chen Ping,Cao Yu,Kang Ya’an,Sun Yichen,Xia Xianghou,Furukawa Kenei,Lu Yu,Wu Min,Huang Qian,Yao Jun,Hawke David H.,Pan Bih-Fang,Zhao Jun,Huang Jiaxing,Wang Huamin,Bahassi EI Mustapha,Stambrook Peter J.,Huang Peng,Fleming Jason B.,Maitra Anirban,Tainer John,Hung Mien-Chie,Chiao Paul J.
Abstract
ABSTRACTPancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of apoptotic pathways. Here, we find that development of anoikis resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often reduced Plk3 expression in human PDAC. Importantly, a 41 kDa Plk3 (p41Plk3) that contained the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase Nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) was quickly removed by proteasome degradation preventing the p41Plk3 inhibition by PBD. We found that p41Plk3 is the activated form of Plk3 that regulates a feedforward mechanism to promote anoikis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn, induces expression of Plk3 and pro-apoptotic genes. These findings uncovered an NRDC-regulated post-translational mechanism (PTM) that activates Plk3, establishing a prototypic regulation by scission mechanism.
Publisher
Cold Spring Harbor Laboratory