The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as an activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions both in vitro and in vivo. Notably, STK25 activates LATS by promoting LATS activation loop phosphorylation independent of a preceding phosphorylation event at the hydrophobic motif, which represents a form of Hippo activation distinct from other kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.

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The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question.Here, we identify the kinase STK25 as a novel activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions. We reveal that STK25 activates LATS via a previously unobserved mechanism, in which STK25 directly phosphorylates the LATS activation loop. This represents a new paradigm in Hippo activation and distinguishes STK25 from all other identified kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.3 First discovered in Drosophila as a critical regulator of organ size, the Hippo tumor suppressor pathway has emerged as playing a major role in maintaining tissue homeostasis through the regulation of cell proliferation and survival (Zanconato et al. 2016). The key mediators of Hippo signaling are LATS1 and LATS2 (Large Tumor Suppressor) kinases, which function to negatively regulate the activity of the oncogenic transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) (Zhang et al. 2009, Zhao et al. 2010. Upon stimulation of Hippo signaling, activated LATS kinases directly phosphorylate YAP/TAZ at conserved serine residues, which promote YAP/TAZ nuclear extrusion and subsequent degradation (Zhao et al. 2010). By contrast, in the absence of LATS activation, YAP/TAZ are free to translocate into the nucleus, where they bind to the TEAD/TEF family of transcription factors to promote the expression of numerous genes essential for cellular proliferation and survival (Wu et al. 2008, Zhang et al. 2008, Hong et al. 2005. Deregulation of LATS1/2 kinases, which leads to subsequent hyper-activation of YAP/TAZ, is sufficient to promote tumorigenesis in mouse models (Zhou et al. 2009, Nishio et al. 2015. Furthermore, amplification of YAP and/or TAZ has been found in a variety of human malignancies (Overholtzer et al. 2006, Fernandez-L et al. 2009).Multiple signals lead to the activation of LATS kinases, including contact inhibition, cellular detachment, loss of actin cytoskeletal tension, serum deprivation, glucose starvation, signaling from G-protein coupled receptors, and cytokinesis failure (Zhao et al. 2010, Dupont et al. 2009, Adler et al. 2013, Mo et al. 2015, Wang et al. 2015, Ganem et al. 2014, Yu et al. 2012, Dutta et al. 2018. Mechanistically, LATS kinases were initially found to be regulated by MST1 and MST2, the mammalian orthologs of the Drosophila Hpo kinase, after which the pathway is named. 4 Activation of LATS1/2...

Mammalian cells are charged with the task of evenly distributing 46 chromosomes to each of two daughter cells during every mitotic cell division. This is achieved by a microtubule‐based cellular structure termed the mitotic spindle. However, numerous cellular and/or genetic defects are known to impair the fidelity of mitosis and promote chromosome segregation errors and aneuploidy. Missegregation of even a single chromosome leads to the deregulated expression of hundreds to thousands of genes, including many that are involved in essential processes such as DNA replication, repair and mitosis. Consequently, while aneuploidy is most typically detrimental to cell viability, it also has the potential to initiate a self‐propagating cycle of chromosome instability that can ultimately promote tumour initiation, progression and relapse. Key Concepts Chromosome segregation is driven by the mitotic spindle. Multiple genetic and/or cell biological defects are known to cause chromosome missegregation and aneuploidy. Aneuploidy is poorly tolerated in normal cells. Cancer cells adapt to tolerate aneuploidy. Cells that persistently missegregate chromosomes are termed chromosomally unstable (CIN). CIN promotes tumour initiation, progression and relapse and correlates with poor patient prognosis. Aneuploidy and CIN are hallmarks of human tumours.