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There are 58 receptor tyrosine kinases (RTK) belonging to 20 subfamilies of RTKs, which localize to the plasma membrane to function as the signal witch and modulating the activity of RTKs has been successfully developed a variety of targeted drugs, such as Iressa®, Tarceva®, Sunitinib®, Herceptin® and Alecensa®. AXL is a receptor-type tyrosine kinase which evolutionally appeared at a late stage. It has been shown that AXL mediate drug resistance in many tumors chemotherapy, but the molecular mechanism remains unclear. In addition, the tyrosine inhibitor targeting AXL, R428, has entered clinic phase I in 2011.

Since 2012, Dr. Fang Wu’s group has initiated their research on the post-translational processing and stability of AXL, by combining the small molecular probes with biochemical approach, and found that the homeostasis of AXL was controlled by alpha-secretase, gamma-secretase and proteasome. Moreover, the AXL receptor can be sequentially cleaved by alpha- and gamma-secretase to produce intracellular domain (ICD) that further modulate the gene expression by a newly identified nuclear localization signal of HRRKK into the nucleus. The preclinical drug, R428, can inhibit the phosphorylation of AXL, and then break the homeostasis of AXL in membrane, which accelerate the AXL cleavage by secretases, and lead to the AXL receptor down-regulation. Inhibition of AXL intramembrane proteolysis mediated by gamma-secretase significantly increase the drug resistance of Tarceva® in non-small cell lung cancer cells. These results suggest that, the tumor drug resistance mediated by AXL may be closely related to the cleavage mediated by secretases. This new discovered post-translational processing of AXL, can provide new targets and ideas for curing the drug resistance in tumor.

This work entitled“Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells” was published online ahead of print in The FASEB Journal ( on 29th December,  2016. It was mainly completed by the PhD student Yinzhong Lu, with the supervision of Dr. Fang Wu. Now, Dr. Fang Wu’s group want to employ this novel mechanism to develop innovative drug leads to specifically accelerate the degradation of AXL, thus hope to provide new methods and therapeutic agents for the treatment of tumor drug resistance. This work was supported by the National Natural Science Foundation of China (31270853, 31300640).


Figure.The steady-state of AXL membrane protein was controlled by alpha secretase, gamma secretase and proteasome. AXL can be cleaved by secretase to produce intracellular fragment ICD, that can be directly transferred into the nucleus.

Copyright: 2013 Young Scientist Laboratory of Shanghai Jiaotong University       Technical Support: Shanghai Yi-chao Information Technology Co., Ltd.