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Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner
Tekijät: Kemppainen K, Wentus N, Lassila T, Laiho A, Tornquist K
Kustantaja: ELSEVIER SCIENCE INC
Julkaisuvuosi: 2016
Lehti: Cellular Signalling
Tietokannassa oleva lehden nimi: CELLULAR SIGNALLING
Lehden akronyymi: CELL SIGNAL
Vuosikerta: 28
Numero: 12
Aloitussivu: 1894
Lopetussivu: 1903
Sivujen määrä: 10
ISSN: 0898-6568
eISSN: 1873-3913
DOI: https://doi.org/10.1016/j.cellsig.2016.09.004
Tiivistelmä
Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid which regulates many cancer-related processes, including cellular proliferation. The Hippo signaling pathway consists of a cascade of tumor suppressive kinases Mst1/2 and Lats1/2 and their downstream targets YAP and TAZ which are generally pro-proliferative transcriptional regulators. Direct phosphorylation by Lats1/2 causes inhibition or degradation of YAP/TAZ and down-regulation of their target genes. We found SPC treatment of MDA-MB-435S breast cancer cells to strongly inhibit their proliferation and to induce a sustained Lats2 protein expression (6-24 h). Therefore, we hypothesized that Hippo signaling might mediate the anti-proliferative SPC response. We also saw a cell density-dependent increase in S127-phosphorylated YAP (pS127-YAP) and a decrease in mRNA levels of YAP target genes (CTGF, Cyr61) in response to long (9 h) SPC treatment. Knockdown of SIP receptor 2 (S1P(2)) prevented the SPC-induced up-regulation of Lats2 and attenuated the anti-proliferative effect of SPC. However, while knockdown of Lats2 alone or in combination with Lats1 expectedly increased basal proliferation it did not attenuate the SPC-induced inhibition of proliferation. Exogenous expression of wild-type or kinase-dead Lats2 and knockdown of YAP/TAZ also had no effect on the anti-proliferative SPC response. It has been previously shown that activation of S1P(2)-G(12/13) by sphingosine-1-phosphate (SIP) leads to rapid de-phosphorylation and up-regulation of YAP. Similarly, we saw a decrease in pS127-YAP and an increase in total YAP levels with short (1 h) SPC treatment as well as a subsequent transient increase in YAP target gene expression. Inhibition of S1P2 prevented the SPC-induced YAP dephosphorylation. The rapid YAP activation and subsequent up-regulation of Lats2 mRNA does not constitute a negative feedback loop as knockdown of YAP/TAZ did not inhibit SPC-induced Lats2 expression. In conclusion, in this study we show that SPC is able to regulate Hippo signaling in a dual and opposite manner, causing an initial activation of YAP followed by an inhibition. However, even the strong SPC-induced effects seen in Lats2 and YAP did not mediate the anti-proliferative SPC response. (C) 2016 Elsevier Inc. All rights reserved.
Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid which regulates many cancer-related processes, including cellular proliferation. The Hippo signaling pathway consists of a cascade of tumor suppressive kinases Mst1/2 and Lats1/2 and their downstream targets YAP and TAZ which are generally pro-proliferative transcriptional regulators. Direct phosphorylation by Lats1/2 causes inhibition or degradation of YAP/TAZ and down-regulation of their target genes. We found SPC treatment of MDA-MB-435S breast cancer cells to strongly inhibit their proliferation and to induce a sustained Lats2 protein expression (6-24 h). Therefore, we hypothesized that Hippo signaling might mediate the anti-proliferative SPC response. We also saw a cell density-dependent increase in S127-phosphorylated YAP (pS127-YAP) and a decrease in mRNA levels of YAP target genes (CTGF, Cyr61) in response to long (9 h) SPC treatment. Knockdown of SIP receptor 2 (S1P(2)) prevented the SPC-induced up-regulation of Lats2 and attenuated the anti-proliferative effect of SPC. However, while knockdown of Lats2 alone or in combination with Lats1 expectedly increased basal proliferation it did not attenuate the SPC-induced inhibition of proliferation. Exogenous expression of wild-type or kinase-dead Lats2 and knockdown of YAP/TAZ also had no effect on the anti-proliferative SPC response. It has been previously shown that activation of S1P(2)-G(12/13) by sphingosine-1-phosphate (SIP) leads to rapid de-phosphorylation and up-regulation of YAP. Similarly, we saw a decrease in pS127-YAP and an increase in total YAP levels with short (1 h) SPC treatment as well as a subsequent transient increase in YAP target gene expression. Inhibition of S1P2 prevented the SPC-induced YAP dephosphorylation. The rapid YAP activation and subsequent up-regulation of Lats2 mRNA does not constitute a negative feedback loop as knockdown of YAP/TAZ did not inhibit SPC-induced Lats2 expression. In conclusion, in this study we show that SPC is able to regulate Hippo signaling in a dual and opposite manner, causing an initial activation of YAP followed by an inhibition. However, even the strong SPC-induced effects seen in Lats2 and YAP did not mediate the anti-proliferative SPC response. (C) 2016 Elsevier Inc. All rights reserved.
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