YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

Abstract

Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients. Cancer Res; 74(16); 4493-503. Ó2014 AACR.

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

“…27 Last, the CDK1 phosphorylates YAP at T119, S128, S138, S289 and S367, which promotes mitotic defects and decreases YAP mediated anti-apoptosis potential induced by the anti-tubulin drugs. 28,29 In the present study, we confirmed most of these post-translational modifications in YAP (Fig. 1) and more interestingly, identified a novel Y188 phosphorylation site and showed that its phosphorylation played a critical role in the regulation of YAP oncogenic functions.…”

“…As shown in Figure 1, we confirmed 4 potential serine phosphorylation sites in YAP1 by Lats1/2 at 61, 109, 127 and 164; 25,26 4 potential phosphorylation sites by JNKs at T119, S138, T154 and S317; 27 and 5 potential phosphorylation sites at T119, S128, S138, S289 and S367 by CDK1. 28,29 More importantly, we identified several additional serine/threonine phosphorylation sites (Fig. 1).…”

Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP

“…It is possible that YAP Ser128 phosphorylation may regulate YAP localization under such conditions. It is worth noting that YAP Ser128 phosphorylation has been observed in many phosphoproteomic studies [25,37,38]. We speculate that YAP Ser128 may be a common regulatory phosphorylation site for proline-directed kinases, such as CDK family and MAP kinase family.…”

“…Notably, the NLK consensus site Ser128 in YAP is adjacent to the Ser127 site and is within the 14-3-3 binding pocket. Previous phosphoproteomic studies also showed that YAP Ser128 is a phosphorylation site [25,37,38]. Thus, we hypothesized that NLK phosphorylates YAP Ser128 to disrupt YAP-14-3-3 binding, leading to the uncoupling event between S127 phosphorylation and cytoplasmic localization.…”

Mechanisms of Hippo pathway regulation

“…YAP and TAZ are phosphorylated at multiple sites by CDK1 during the G2/M phase of the cell cycle (Yang et al 2013(Yang et al , 2015bZhao et al 2014;Dent et al 2015;Zhao and Yang 2015). However, the physiological outcomes of these phosphorylation events are rather perplexing, as their effects on cell growth and migration are not entirely consistent among reports from different groups.…”