Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism.
Suppressor of Fused (SuFu) plays a conservative role in the regulation of the Gli transcription factors within the Hedgehog (Hh) signaling pathway. Despite the central importance of SuFu in the Hh pathway, little is known about its regulation. Here, we performed a GAL4-based yeast two-hybrid screen using human SuFu as bait, and identified NIMA-related expressed kinase 2A (Nek2A) as a new SuFu-interacting protein, which was also confirmed by glutathione-S-transferase pull-down and co-immunoprecipitation assays. Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein. Moreover, the phosphorylated SuFu inhibits the nuclear localization and transcriptional activity of Gli2/Hh signaling. These findings reveal a new mechanism of mammalian SuFu regulation, and offers novel insights into Hh signaling regulation in development and human disease.
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, China.
Yao
Y
Wang
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Yong
Y
Li
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, China.
Guanghui
G
Hu
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Xuan
X
Huang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Hai
H
Rao
School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, China.
Xiangyang
X
Xiong
School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, China.
Zhijun
Z
Luo
Department of Biostatistics & Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006, China.
Quqin
Q
Lu
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Jiangxi Key Laboratory of Molecular Diagnostics and Precision Medicine, China. Electronic address: shiwenluo@ncu.edu.cn.
Shiwen
S
Luo
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000072379:NIMA-Related Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055550:Protein Stability; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D000075746:Zinc Finger Protein Gli2 / Q000378:metabolism*
C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D000075746:Zinc Finger Protein Gli2; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases
Hedgehog signaling pathway; NIMA-related expressed kinase 2A; Phosphorylation; Suppressor of fused; Transcription factor Gli2