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Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner.
Cell Signal. 2016 12; 28(12):1894-1903.CS

Abstract

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 (6-24h). 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 (9h) SPC treatment. Knockdown of S1P receptor 2 (S1P2) 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 S1P2-G12/13 by sphingosine-1-phosphate (S1P) 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 (1h) SPC treatment as well as a subsequent transient increase in YAP target gene expression. Inhibition of S1P2 prevented the SPC-induced YAP de-phosphorylation. 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.

Authors+Show Affiliations

Department of Biosciences, Åbo Akademi University; Tykistökatu 6, 20520 Turku, Finland.Department of Biosciences, Åbo Akademi University; Tykistökatu 6, 20520 Turku, Finland.Department of Biosciences, Åbo Akademi University; Tykistökatu 6, 20520 Turku, Finland.Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland.Department of Biosciences, Åbo Akademi University; Tykistökatu 6, 20520 Turku, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland. Electronic address: ktornqvi@abo.fi.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27634386

Citation

Kemppainen, Kati, et al. "Sphingosylphosphorylcholine Regulates the Hippo Signaling Pathway in a Dual Manner." Cellular Signalling, vol. 28, no. 12, 2016, pp. 1894-1903.
Kemppainen K, Wentus N, Lassila T, et al. Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner. Cell Signal. 2016;28(12):1894-1903.
Kemppainen, K., Wentus, N., Lassila, T., Laiho, A., & Törnquist, K. (2016). Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner. Cellular Signalling, 28(12), 1894-1903. https://doi.org/10.1016/j.cellsig.2016.09.004
Kemppainen K, et al. Sphingosylphosphorylcholine Regulates the Hippo Signaling Pathway in a Dual Manner. Cell Signal. 2016;28(12):1894-1903. PubMed PMID: 27634386.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosylphosphorylcholine regulates the Hippo signaling pathway in a dual manner. AU - Kemppainen,Kati, AU - Wentus,Nina, AU - Lassila,Taru, AU - Laiho,Asta, AU - Törnquist,Kid, Y1 - 2016/09/12/ PY - 2016/01/07/received PY - 2016/08/22/revised PY - 2016/09/11/accepted PY - 2016/9/17/pubmed PY - 2017/9/30/medline PY - 2016/9/17/entrez KW - Lats2 KW - Proliferation KW - S1P(2) KW - Sphingosylphosphorylcholine KW - Yap SP - 1894 EP - 1903 JF - Cellular signalling JO - Cell. Signal. VL - 28 IS - 12 N2 - 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 (6-24h). 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 (9h) SPC treatment. Knockdown of S1P receptor 2 (S1P2) 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 S1P2-G12/13 by sphingosine-1-phosphate (S1P) 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 (1h) SPC treatment as well as a subsequent transient increase in YAP target gene expression. Inhibition of S1P2 prevented the SPC-induced YAP de-phosphorylation. 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. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/27634386/Sphingosylphosphorylcholine_regulates_the_Hippo_signaling_pathway_in_a_dual_manner_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(16)30230-3 DB - PRIME DP - Unbound Medicine ER -