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.

Tetraploidy has long been proposed as an intermediate cellular stage en route to the aneuploidy and chromosomal instability that is observed in many cancer types. Although tetraploidy has been shown to be an unstable cellular state, an in depth analysis of the effect of a spontaneous tetraploidisation event on the cancer genome has not been carried out. Using an isogenic system of naturally occurring tetraploid cells derived from a chromosomally stable colorectal cancer cell line, the effect of tetraploidisation on genome stability over time was assessed. Tetraploid cells were shown to have increased structural and numerical instability on a per cell but not per chromosome basis. Over time the tetraploid genome became increasingly genomically unstable, which is likely due to the increased ability of tetraploid clones to propagate segregation errors. The genomic landscape of tetraploid clones began to recapitulate the genomic architecture of chromosomally unstable colorectal cancer, and allowed for the selection of clinically high risk chromosomal losses over time. Genome doubling was further shown to be a predictive marker of poor prognosis in colorectal cancer. Exhaustive analysis of DNA and mRNA failed to reveal any common changes in tetraploid clones that are likely to explain their aneuploidy tolerance phenotype. Instead a focussed siRNA screen of genes commonly mutated in genome-doubled tumours of multiple cancer types was carried out. Given the high-risk clinical phenotypes associated with tetraploidy and chromosomal instability, it remains a priority to identify the mechanisms allowing tumour cells to undergo tetraploidisation and to sustain chromosome segregation errors.

Whole genome doubling propagates chromosomal instability and accelerates cancer genome evolution

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.

This chapter discusses the pathophysiological mechanisms and contributing factors underlying the etiology of carpal tunnel syndrome. The etiology of carpal tunnel syndrome is complex and still has not been fully elucidated. Many factors have been implicated in the development and progression of carpal tunnel syndrome. Injury due to repetitive mechanical stress and resulting nerve injury has been historically thought to be the cause of carpal tunnel syndrome. Additionally, systemic disease states including diabetes, acromegaly, thyroid dysfunction, and rheumatoid arthritis among others have been linked to carpal tunnel syndrome. Age, gender, and genetic factors have also been associated with the development of carpal tunnel syndrome. The various elements that may predispose to carpal tunnel syndrome have been explored in depth in this chapter.

Pathophysiology of Carpal Tunnel Syndrome

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.




Keywords:

centrosome;
micronucleus;
merotelic;
cohesion;
spindle assembly checkpoint;
tetraploidy;
lagging chromosome

Mitosis: Chromosome Segregation and Stability

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

Hatim M. Mustaly

Papers

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

Pathophysiology of Carpal Tunnel Syndrome

Mitosis: Chromosome Segregation and Stability

Identification of STK25 as a direct activator of LATS signaling

STK25 directly activates LATS1/2 independent of MST/MAP4Ks