The Hippo signalling pathway

Introduction

The Hippo signalling pathway controls tissue growth, and it is also a vital pathway involved in many cancers. It is a serine/threonine kinase pathway, which regulates tissue growth by the control of cell proliferation and apoptosis. It was first discovered in a Drosophila genetic screen and was named Hippo, as a loss of Hippo results in an overgrowth (or hippopotamus) phenotype.  

When the Hippo pathway is ‘on,’ YAP and TAZ (transcription factors/activators) are degraded in the cytoplasm. This occurs via phosphorylation: Sterile 20-related (MST) kinases are phosphorylated, which in turn phosphorylate Large tumour suppressor 1 and 2 (LATS1/2). LATS phosphorylation then causes phosphorylation of YAP/TAZ. In turn, YAP/TAZ then bind to 14-3-3 proteins in the cytoplasm and are broken down by ubiquitin-dependent degradation (see fig. 1). YAP/TAZ has also been shown to activate transcription of YAP/TAZ regulators, such as LATS1/2, in a negative feedback loop. Conversely, when Hippo is ‘off,’ YAP/TAZ are unphosphorylated and are free to move to the nucleus, where they bind to Transcriptional enhanced associate domain (TEAD). YAP/TAZ-TEAD then are able to bind DNA and be involved in transcription of genes such as Axl, c-Myc, survivin, CTGF, and Cyr61, which are anti-apoptotic or proliferative. 

Hippo pathway in cancer

YAP/TAZ have been shown to be crucial for cancer initiation, progression, and metastasis. They are known to be involved in many cancers, including prostate, bone, eye, brain, spinal cord, breast, and liver cancers. They are also involved in the rare blood vessel cancer epithelioid hemangioendothelioma (EHE). Interestingly, it appears YAP/TAZ act differently depending on the cell type. YAP/TAZ are oncogenic transcription factors in many solid tumours, but surprisingly, they are thought to act as tumour suppressors in some blood cancers e.g. Multiple myeloma (it is still unknown why this is). Therefore, for YAP/TAZ to behave in a regular manner (i.e. non-oncogenic), they must be tightly regulated.  

Regulation of the Hippo pathway

Hippo signalling is regulated by tight/adherens junctions, mechanical signals, and growth factors/receptors. Tight junctions exist where there is a permeability barrier between adjoining cells, and proteins bind to these membranes for a range of different functions. A protein which binds to these adherens junctions is Merlin (encoded by the gene, NF2), which is another regulator of the Hippo pathway and a well-known tumour suppressor. Merlin is known to bind to adherens junction proteins in confluent cells, and loss of Merlin causes a lack of development of adherens junctions. Merlin is also an important component involved in contact inhibition during proliferation. Contact inhibition is where cell growth is inhibited upon contact with other cells. The specific mechanism by which Merlin regulates the Hippo pathway and contact inhibition is still unknown. 

Another regulator of the Hippo pathway is mechanical signals. Fluid shear stress is the frictional force between flowing blood and endothelial cells lining the blood vessels and is known to cause vascular growth, remodelling and maintenance. This stress can result in changes to endothelial cell shape and cause the activation of transcription factors, leading to gene expression.  

An additional regulator of the Hippo pathway is growth factors/receptors. Growth factors, such as Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are both part of the phospholipids growth factor family.  They bind to the S1P receptor and LPA receptor, respectively, inhibiting LATS and causing activation of YAP/TAZ. Whereas molecules, such as glucagon and epinephrine have been shown to suppress YAP/TAZ. Cytokines, vascular endothelial growth factors (VEGF), epidermal growth factors (EGF), Wnt, bone morphogenic protein (Bmp), insulin, and transforming growth factor β (TGF-β) have also been shown to regulate the Hippo pathway, which suggests that regulation of the Hippo pathway is complex and linked to several different other pathways.

Conclusion

The Hippo pathway is a vitally important pathway regulating tissue growth. YAP/TAZ, which are part of the Hippo pathway, are oncogenic factors in many solid tumours but can act as tumour suppressors in some blood cancers. As YAP/TAZ are involved in transcription in this pathway, they are crucial for cancer initiation, growth and metastasis. Hence, targeting of this pathway could lead to further cancer treatments. For example, TEAD inhibitors may offer a therapeutic avenue of treatment and are currently being investigated. In the future, further research on targeting the Hippo pathway may improve on the current targeted therapeutic landscape, realising the need for diverse treatment options for such a complex disease as cancer.

Written by Eleanor R. Markham

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