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Mol Cells. 2019 Aug 31;42(8):604-616. doi: 10.14348/molcells.2019.0160.

Phosphoserine Phosphatase Promotes Lung Cancer Progression through the Dephosphorylation of IRS-1 and a Noncanonical L-Serine-Independent Pathway.

Park SM1,2,3, Seo EH4,5,3, Bae DH4,5,3, Kim SS6,2,3, Kim J1,4, Lin W6,2, Kim KH6,2, Park JB6,2, Kim YS4,5, Yin J7,6,2, Kim SY1,5.

Author information

1
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Korea.
2
Research Institute, National Cancer Center, Goyang 10408, Korea.
3
These authors contributed equally to this work.
4
Genome Editing Research Center, KRIBB, Daejeon 34141, Korea.
5
Department of Bioscience, University of Science and Technology, Daejeon 34113, Korea.
6
Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.
7
Henan and Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng 475004, China.

Abstract

Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers in an L-serine synthesis-independent manner, but the mechanism remains elusive. We demonstrate that PSPH promotes lung cancer progression through a noncanonical L-serine-independent pathway. PSPH was significantly associated with the prognosis of lung cancer patients and regulated the invasion and colony formation of lung cancer cells. Interestingly, L-serine had no effect on the altered invasion and colony formation by PSPH. Upon measuring the phosphatase activity of PSPH on a serine-phosphorylated peptide, we found that PSPH dephosphorylated phospho-serine in peptide sequences. To identify the target proteins of PSPH, we analyzed the protein phosphorylation profile and the PSPH-interacting protein profile using proteomic analyses and found one putative target protein, IRS-1. Immunoprecipitation and immunoblot assays validated a specific interaction between PSPH and IRS1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells. We suggest that the specific interaction and dephosphorylation activity of PSPH have novel therapeutic potential for lung cancer treatment, while the metabolic activity of PSPH, as a therapeutic target, is controversial.

KEYWORDS:

IRS-1; L-serine independent pathway; lung cancer; phosphoserine phosphatase

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