The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells.
The control of breast cell survival is of critical importance for preventing breast cancer initiation and progression. The activity of many proteins which regulate cell survival is controlled by reversible phosphorylation, so that the relevant kinases and phosphatases play crucial roles in determining cell fate. Several protein kinases act as oncoproteins in breast cancer and changes in their activities contribute to the process of transformation. Through counteracting the activity of oncogenic kinases, the protein phosphatases are also likely to be important players in breast cancer development, but this class of molecules is relatively poorly understood. Here we have investigated the role of the serine/threonine protein phosphatase 4 in the control of cell survival of breast cancer cells.



The breast cancer cell lines, MCF7 and MDA-MB-231, were transfected with expression vectors encoding the catalytic subunit of protein phosphatase 4 (PP4c) or with PP4c siRNAs. Culture viability, apoptosis, cell migration and cell cycle were assessed. The involvement of phosphoprotein enriched in astrocytes 15kDa (PEA15) in PP4c action was investigated by immunoblotting approaches and by siRNA-mediated silencing of PEA15.



In this study we showed that PP4c over-expression inhibited cell proliferation, enhanced spontaneous apoptosis and decreased the migratory and colony forming abilities of breast cancer cells. Moreover, PP4c down-regulation produced complementary effects. PP4c is demonstrated to regulate the phosphorylation of PEA15, and PEA15 itself regulates the apoptosis of breast cancer cells. The inhibitory effects of PP4c on breast cancer cell survival and growth were lost in PEA15 knockdown cells, confirming that PP4c action is mediated, at least in part, through the de-phosphorylation of apoptosis regulator PEA15.



Our work shows that PP4 regulates breast cancer cell survival and identifies a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. The dysfunction of this axis may be important in the development and progression of breast cancer.
School of Life Sciences, Faculty of Natural Sciences, Keele University, Keele, Staffordshire ST5 5BG, United Kingdom. Electronic address: h.n.mohammed@keele.ac.uk.
Hiba N
HN
Mohammed
Institute of Medicine, University of Chester, Chester CH2 1BR, United Kingdom. Electronic address: m.pickard@chester.ac.uk.
Mark R
MR
Pickard
School of Life Sciences, Faculty of Natural Sciences, Keele University, Keele, Staffordshire ST5 5BG, United Kingdom. Electronic address: m.m.maarabouni@keele.ac.uk.
Mirna
M
Mourtada-Maarabouni
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D010768:Phosphoserine; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4
PEA15, cell survival; PP4; PP4c; breast cancer