Open AccessNEDD 4‐induced degradative ubiquitination of phosphatidylinositol 4‐phosphate 5‐kinase α and its implication in breast cancer cell proliferation
Author(s) -
Tran Mai Hoang,
Seo Eunjeong,
Min Soohong,
Nguyen QuynhAnh T.,
Choi Juyong,
Lee UkJin,
Hong SoonSun,
Kang Hyuk,
Mansukhani Alka,
Jou Ilo,
Lee Sang Yoon
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13689
Subject(s) - phosphatidylinositol , protein kinase b , ubiquitin ligase , cell growth , pi3k/akt/mtor pathway , kinase , chemistry , microbiology and biotechnology , ubiquitin , biology , phosphorylation , signal transduction , biochemistry , gene
Phosphatidylinositol 4‐phosphate 5‐kinase ( PIP 5K) family members generate phosphatidylinositol 4,5‐bisphosphate ( PIP 2), a critical lipid regulator of diverse physiological processes. The PIP 5K‐dependent PIP 2 generation can also act upstream of the oncogenic phosphatidylinositol 3‐kinase ( PI 3K)/Akt pathway. Many studies have demonstrated various mechanisms of spatiotemporal regulation of PIP 5K catalytic activity. However, there are few studies on regulation of PIP 5K protein stability. Here, we examined potential regulation of PIP 5Kα, a PIP 5K isoform, via ubiquitin‐proteasome system, and its implication for breast cancer. Our results showed that the ubiquitin ligase NEDD 4 (neural precursor cell expressed, developmentally down‐regulated gene 4) mediated ubiquitination and proteasomal degradation of PIP 5Kα, consequently reducing plasma membrane PIP 2 level. NEDD 4 interacted with the C‐terminal region and ubiquitinated the N‐terminal lysine 88 in PIP 5Kα. In addition, PIP 5Kα gene disruption inhibited epidermal growth factor ( EGF )‐induced Akt activation and caused significant proliferation defect in breast cancer cells. Notably, PIP 5Kα K88R mutant that was resistant to NEDD 4‐mediated ubiquitination and degradation showed more potentiating effects on Akt activation by EGF and cell proliferation than wild‐type PIP 5Kα. Collectively, these results suggest that PIP 5Kα is a novel degradative substrate of NEDD 4 and that the PIP 5Kα‐dependent PIP 2 pool contributing to breast cancer cell proliferation through PI 3K/Akt activation is negatively controlled by NEDD 4.