The Hippo signalling pathway is gaining recognition as an important player in tumor progression. Components of the pathway, which include transcriptional co-activators YAP/TAZ, are dysregulated in a significant fraction of human cancers, and YAP activation has recently been shown to promote Epithelial to Mesenchymal Transition (EMT) and metastasis. However, how Hippo signalling is dysregulated in tumors remains unclear. Here, we demonstrate that Integrin-Linked Kinase (ILK), an actin-interacting, focal adhesion adaptor and serine/threonine protein kinase whose expression is also significantly upregulated in many types of cancers, inhibits the Hippo tumor suppressor pathway by stimulating the phosphorylation, and inhibiting the activity of Merlin, via the protein phosphatase inhibitor, CPI-17, an established target of ILK, and an inhibitor of Merlin (Deng JT et al. Biochem J 2002; Huang J et al. Biochem J 2006). We have assessed the pathway in human breast and prostate cancer cell lines, in which the Hippo pathway is switched OFF, as determined by the phosphorylation status of Merlin, MST1/2, LATS1/2, and YAP, and the nuclear YAP localization. We demonstrate that inhibition of ILK expression, or inhibition of its activity in these cells turns the Hippo pathway ON, resulting in the stimulation of YAP phosphorylation, sequestration in the cytoplasm, and inhibition of TEAD transcriptional activity. In addition, we have determined that YAP/TAZ protein expression is significantly upregulated in vivo in ErbB2 induced mammary tumors from transgenic mice, and that deletion of ILK from these tumors, which significantly delays tumor growth and inhibits metastasis, dramatically suppresses the expression of these transcription co-activators. Finally, we demonstrate that ILK plays a critical role in the suppression of the Hippo pathway by TGF-b, EGF and LPA. Treatment of human breast and prostate epithelial cells with these growth factors results in dephosphorylation of LATS 1/2, and YAP, and nuclear localization of YAP. However, inhibiting ILK activity under these conditions results in the stimulation of phosphorylation of LATS1/2 and YAP, as well as in the sequestration of YAP/TAZ in the cytoplasm. These novel data demonstrate that ILK inhibits the Hippo tumor suppressor pathway leading to nuclear activation of YAP/TAZ, thereby contributing to tumor progression and metastasis.
Citation Format: Isabel Serrano, William J. Muller, Shoukat Dedhar. Integrin-Linked Kinase (ILK) breaks Merlin's spell to inhibit the Hippo tumor suppressor pathway and activate the YAP oncogene. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2013-769