title: NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling.
abstract: Oncogenic PIK3CA (p110α), the catalytic subunit of class IA PI3K, plays a major role in PI3K-related cancer progression. The mechanisms underlying the dynamic regulation of PIK3CA protein levels remain unknown. Here we demonstrated that PIK3CA is regulated by polyubiquitination. We identified NEDD4L as the E3 ligase that catalyzes PIK3CA polyubiquitination, leading to its proteasome-dependent degradation. NEDD4L ubiquitinates both the free and regulatory subunit-bound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. Overexpression of NEDD4L accelerates the turnover rate of PIK3CA, whereas suppression of NEDD4L results in not only the accumulation of PIK3CA but also a paradoxical decrease of AKT activation. Thus, we propose that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway.
authors.affiliation: From the Division of Cell Biology, College of Life Sciences, and Joint Center for Life Sciences, Peking University, Yiheyuan Road No. 5, Haidian District, Beijing 100871, China and.
authors.forename: Zixi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Division of Cell Biology, College of Life Sciences, and Joint Center for Life Sciences, Peking University, Yiheyuan Road No. 5, Haidian District, Beijing 100871, China and.
authors.forename: Tingting
authors.initials: T
authors.lastname: Dang
authors.affiliation: From the Division of Cell Biology, College of Life Sciences, and Joint Center for Life Sciences, Peking University, Yiheyuan Road No. 5, Haidian District, Beijing 100871, China and.
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: From the Division of Cell Biology, College of Life Sciences, and Joint Center for Life Sciences, Peking University, Yiheyuan Road No. 5, Haidian District, Beijing 100871, China and min.fang@pku.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
mesh_terms: D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt PKB; E3 ubiquitin ligase; NEDD4L; PIK3CA; phosphatidylinositide 3-kinase (PI 3-kinase); proteasome; protein degradation; ubiquitylation (ubiquitination)