The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1.
We previously performed an RNA interference (RNAi) screen and found that the knockdown of the catalytically inactive phosphatase, MK-STYX [MAPK (mitogen-activated protein kinase) phospho-serine/threonine/tyrosine-binding protein], resulted in potent chemoresistance. Our follow-up studies demonstrated that knockdown of MK-STYX prevents cells from undergoing apoptosis through a block in cytochrome c release, but that MK-STYX does not localize proximal to the molecular machinery currently known to control this process. In an effort to define its molecular mechanism, we utilized an unbiased proteomics approach to identify proteins that interact with MK-STYX. We identified the mitochondrial phosphatase, PTPMT1 (PTP localized to mitochondrion 1), as the most significant and unique interaction partner of MK-STYX. We previously reported that knockdown of PTPMT1, an important component of the cardiolipin biosynthetic pathway, is sufficient to induce apoptosis and increase chemosensitivity. Accordingly, we hypothesized that MK-STYX and PTPMT1 interact and serve opposing functions in mitochondrial-dependent cell death. We confirmed that MK-STYX and PTPMT1 interact in cells and, importantly, found that MK-STYX suppresses PTPMT1 catalytic activity. Furthermore, we found that knockdown of PTPMT1 resensitizes MK-STYX knockdown cells to chemotherapeutics and restores the ability to release cytochrome c. Taken together, our data support a model in which MK-STYX controls apoptosis by negatively regulating PTPMT1. Given the important role of PTPMT1 in the production of cardiolipin and other phospholipids, this raises the possibility that dysregulated mitochondrial lipid metabolism may facilitate chemoresistance.
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Natalie M
NM
Niemi
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Juliana L
JL
Sacoman
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Laura M
LM
Westrate
Developmental and Molecular Pathways Department, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
L Alex
LA
Gaither
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Nathan J
NJ
Lanning
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Katie R
KR
Martin
Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Jeffrey P
JP
MacKeigan
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
D051017:Apoptosis Regulatory Proteins; C558168:STYXL1 protein, human; D051059:PTEN Phosphohydrolase