Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409

• Published in: The Journal of biological chemistry 2015-01, Vol.290 (5), p.3149-3160
• Main Authors: Deng, Si-Si, Wu, Le-Yu, Wang, Ya-Chao, Cao, Peng-Rong, Xu, Lei, Li, Qian-Ru, Liu, Meng, Zhang, Lun, Jiang, Yue-Jing, Yang, Xiao-Yu, Sun, Sheng-Nan, Tan, Min-jia, Qian, Min, Zang, Yi, Feng, Linyin, Li, Jia
• Format: Article
• Language: English
• Subjects: Animals; Cell Biology; Cyclic AMP-Dependent Protein Kinases - metabolism; HEK293 Cells; Humans; MARK2; Microtubule; Microtubule-associated Protein (MAP); Microtubules - metabolism; Neurite Outgrowth; Neurites - metabolism; Phosphorylation; Protein Kinase A (PKA); Protein-Serine-Threonine Kinases - metabolism; Rats; Serine - metabolism; Tau Protein (Tau)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.629873

Microtubule affinity-regulating kinase 2 (MARK2)/PAR-1b and protein kinase A (PKA) are both involved in the regulation of microtubule stability and neurite outgrowth, but whether a direct cross-talk exists between them remains unclear. Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. PKA could not reverse the microtubule disruption effect induced by a serine 409 to alanine (Ala) mutant of MARK2 (MARK2 S409A). In contrast, mutation of MARK2 serine 409 to glutamic acid (Glu) (MARK2 S409E) did not affect microtubule stability and neurite outgrowth. We propose that PKA functions as an upstream inhibitor of MARK2 in regulating microtubule stability and neurite outgrowth by directly interacting and phosphorylating MARK2. Background: MARK2 and PKA are both involved in the regulation of microtubule stability. Results: PKA significantly inhibits MARK2 by phosphorylating serine 409 and rescues MARK2-induced microtubule instability and neurite disruption. Conclusion: PKA functions as an upstream inhibitor of MARK2 by directly interacting and phosphorylating it. Significance: The results identify a novel interaction between PKA and MARK2, providing new insight into the signal networks of both.