The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

Abstract

<p class="first" id="d4733581e308">The mammalian STE20-like protein kinase 1 (MST1)–MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST–MOB complexes are also involved in regulating Hippo–YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4–MOB4 complex resembles that of the MST1–MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1–MOB1 complex, the MST4–MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1–MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4–MOB4 complex as a noncanonical regulator of the Hippo–YAP pathway with an oncogenic role in PC. Our findings highlight that although MST–MOB complexes display some structural conservation, they functionally diverged during their evolution. </p>