STK25 directly activates LATS1/2 independent of MST/MAP4Ks

Abstract

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...

Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options

“…Highlighting the importance of YAP/TAZ regulation, previous studies have shown that LATS1/2 can be activated in an MST1/2‐independent way by mitogen‐activated protein kinase kinase kinase kinase 1–7 (MAP 4K1–7) 47 . These enzymes act by phosphorylating LATS1/2 in its hydrophobic motif 48 .…”

“…These enzymes act by phosphorylating LATS1/2 in its hydrophobic motif 48 . Moreover, the Serine/Threonine Kinase 25 (STK25) was also shown to activate LATS1/2 by direct phosphorylation of the activation loop motif 47 . The redundancy of enzymes which activate LATS1/2 and the different ways of its activation indicate LATS1/2 is a central regulator of YAP/TAZ activity that needs to be tightly regulated in order to maintain homeostasis and normal development.…”