TY - JOUR
T1 - NEDD4L protein catalyzes ubiquitination of PIK3CA protein and regulates PI3K-AKT signaling
AU - Wang, Zixi
AU - Dang, Tingting
AU - Liu, Tingting
AU - Chen, She
AU - Li, Lin
AU - Huang, Song
AU - Fang, Min
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/8/12
Y1 - 2016/8/12
N2 - 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 subunitbound 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.
AB - 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 subunitbound 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.
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U2 - 10.1074/jbc.M116.726083
DO - 10.1074/jbc.M116.726083
M3 - Article
C2 - 27339899
AN - SCOPUS:84981295785
SN - 0021-9258
VL - 291
SP - 17467
EP - 17477
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 33
ER -