DAPK and CIP2A are involved in GAS6/AXL-mediated Schwann cell proliferation in a rat model of bilateral cavernous nerve injury

// Yen-Lin Chen 1, 2, 3 , Yi-Ting Tsai 1 , Ting-Ting Chao 4 , Yi-No Wu 5 , Meng-Chuan Chen 6 , Ying-Hung Lin 3 , Chun-Hou Liao 3, 7 , Shang-Shing P. Chou 2 and Han-Sun Chiang 3, 7 1 Department of Pathology, Cardinal Tien Hospital, New Taipei, Taiwan 2 Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan 3 Graduate Institute of Biomedical and Pharmaceutical Science, Fu-Jen Catholic University, New Taipei, Taiwan 4 Medical Research Center, Cardinal Tien Hospital, New Taipei, Taiwan 5 School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan 6 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 7 Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, Taiwan Correspondence to: Han-Sun Chiang, email: 05382@mail.fju.edu.tw Keywords: cavernous nerve; Schwann cell; CIP2A; DAPK; GAS6/AXL Received: July 22, 2017 Accepted: October 28, 2017 Published: January 05, 2018 ABSTRACT Purpose: Impotence is one of the major complications occurring in prostate cancer patients after radical prostectomy (RP). Self-repair of the injured nerve has been observed in animal models and in patients after RP. However, the downstream signalling is not well documented. Here, we found that the DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation. Materials and Methods: The 3 groups were a sham group, a 14-day post-bilateral cavernous nerve injury (BCNI) group and a 28-day post-BCNI group. Erectile function was assessed and immunohistochemistry was performed. The rat Schwann cell RSC96 line was chosen for gene knockdown, cell viability, western blot, immunofluorescence and co-immunoprecipitation assays. Results: The intracavernosal pressure was low on the 14 th day after BCNI and partially increased by the 28 th day. GAS6 and p-AXL expression gradually increased in the cavernous nerve after BCNI. RSC96 cells incubated with a GAS6 ligand showed increased levels of p-ERK1/2 and p-AKT. Moreover, DAPK and CIP2A.p-AXL and p-DAPK and CIP2A complexes were identified by both immunoblotting and co-immunoprecipitation. Conclusion: The DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation. CIP2A inhibits PP2A activity, which results in p-DAPK(S308) maintenance and promotes Schwann cell proliferation. CIP2A is a potential target for the treatment of nerve injury after RP.