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Sphingosine 1-phosphate receptor 4 uses HER2 (ErbB2) to regulate extracellular signal regulated kinase-1/2 in MDA-MB-453 breast cancer cells

Long, J.S. and Fujiwara, Y. and Edwards, J. and Tannahill, C.L. and Tigyi, G. and Pyne, S. and Pyne, N.J. (2010) Sphingosine 1-phosphate receptor 4 uses HER2 (ErbB2) to regulate extracellular signal regulated kinase-1/2 in MDA-MB-453 breast cancer cells. Journal of Biological Chemistry, 285. pp. 35957-35966. ISSN 0021-9258

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Abstract

We demonstrate here that the bioactive lipid sphingosine 1-phosphate (S1P) uses the sphingosine 1-phosphate receptor 4 (S1P4) and human epidermal growth factor receptor 2 (HER2) to stimulate the extracellular signal regulated protein kinase 1/2 (ERK-1/2) pathway in MDA-MB-453 cells. This was based on several lines of evidence. First, the S1P stimulation of ERK-1/2 was abolished by JTE013, which we show here is an S1P2/4 antagonist and reduced by siRNA knock down of S1P4. Second, the S1P-stimulated activation of ERK-1/2 was almost completely abolished by a HER2 inhibitor (ErbB2 inhibitor II) and reduced by siRNA knock down of HER2 expression. Third, phyto-S1P, which is an S1P4 agonist, stimulated ERK-1/2 activation in an S1P4- and HER2-dependent manner. Fourth, FTY720 phosphate which is an agonist at S1P1, 3, 4, 5 but not S1P2 stimulated activation of ERK-1/2. Fifth, S1P stimulated the tyrosine phosphorylation of HER2, which was reduced by JTE013. HER2 which is an orphan receptor tyrosine kinase is the preferred dimerisation partner of the EGF receptor. However, EGF-stimulated activation of ERK-1/2 was not affected by siRNA knock down of HER2 or by ErbB2 inhibitor II in MDA-MB-453 cells. Moreover, S1P-stimulated activation of ERK-1/2 does not require EGF receptor. Thus, S1P and EGF function in a mutually exclusive manner. In conclusion, the magnitude of the signaling gain on the ERK-1/2 pathway produced in response to S1P can be increased by HER2 in MDA-MB-453 cells. The linkage of S1P with an oncogene suggests that S1P and specifically S1P4 may have an important role in breast cancer progression.