https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5031&context=oapubs

Control of cellular responses to mechanical cues through YAP/TAZ regulation.

https://www.cell.com/immunity/pdf/S1074-7613(20)30073-X.pdf

mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury.

https://www.pure.ed.ac.uk/ws/files/124058716/PIIS0962892419301680.pdf

The Hippo Pathway, YAP/TAZ and the Plasma Membrane

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) are the downstream effectors of the Hippo signaling pathway that play a crucial role in various aspects of cancer progression including metastasis. Metastasis is the multistep process of disseminating cancer cells in a body and responsible for the majority of cancer-related death. Emerging evidence has shown that cancer cells reprogram their metabolism to gain proliferation, invasion, migration, and anti-apoptotic abilities and adapt to various environment during metastasis. Moreover, it has increasingly been recognized that YAP/TAZ regulates cellular metabolism that is associated with the phenotypic changes, and recent studies suggest that the YAP/TAZ-mediated metabolic alterations contribute to metastasis. In this review, we will introduce the latest knowledge of YAP/TAZ regulation and function in cancer metastasis and metabolism, and discuss possible links between the YAP/TAZ-mediated metabolic reprogramming and metastasis.

/pdf/a-potential-role-of-yap-taz-in-the-interplay-between-4ia9ul9ige.pdf

A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations.

Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings. 

/pdf/the-hippo-pathway-in-cancer-yap-taz-and-tead-as-therapeutic-jv3lar2v.pdf

The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer

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. Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.

/pdf/identification-of-the-kinase-stk25-as-an-upstream-activator-3ntti57foy.pdf

Identification of the kinase STK25 as an upstream activator of LATS signaling.

LATS kinases integrate numerous cellular cues to restrict the oncoproteins YAP/TAZ in a phosphorylation-dependent fashion as part of the Hippo tumor suppressor pathway, yet upstream activators of LATS kinases remain incompletely characterized. We performed a focused RNAi-based kinome screen and identified the kinase STK25 as a previously uncharacterized activator of LATS. We demonstrate that loss of STK25 blunts the ability of cells to activate Hippo signaling and is sufficient to significantly increase levels of active YAP/TAZ to enhance cellular proliferation. In contrast to all known kinase activators of LATS, which phosphorylate the hydrophobic motif of LATS kinases to stimulate auto-phosphorylation, STK25 directly phosphorylates the activation loop motif of LATS. Interestingly, STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a major mechanism by which tumors are able to functionally impair the Hippo tumor suppressor pathway.

https://www.biorxiv.org/content/biorxiv/early/2018/10/01/354233.full.pdf

Identification of STK25 as a direct activator of LATS signaling

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.

/pdf/stk25-directly-activates-lats1-2-independent-of-mst-map4ks-233mh1kdt2.pdf

Ian Paolo Morelos Mauricio

Papers

Identification of the kinase STK25 as an upstream activator of LATS signaling.

Identification of STK25 as a direct activator of LATS signaling

STK25 directly activates LATS1/2 independent of MST/MAP4Ks