Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo signaling is responsible for cancer growth, invasion, and metastasis. In this short review, we will explore whether the Hippo pathway is an important regulator of skin carcinogenesis and if it could be a promising target for future therapies.

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Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

10.1101/2020.07.08.192765 ◽

2020 ◽

Author(s):

Sherzod A. Tokamov ◽

Ting Su ◽

Anne Ullyot ◽

Richard G. Fehon

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Hippo Pathway ◽

Tissue Growth ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

The Core ◽

Pathway Activation ◽

The Hippo Pathway ◽

Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

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SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽

10.7554/elife.30278 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 42

Author(s):

Sung Jun Bae ◽

Lisheng Ni ◽

Adam Osinski ◽

Diana R Tomchick ◽

Chad A Brautigam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Hippo Pathway ◽

Tissue Growth ◽

Activation Loop ◽

Hippo Signaling ◽

Ww Domains ◽

Kinase Activation ◽

Genetic Ablation ◽

Kinase Cascade ◽

The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

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Nerfin-1 represses transcriptional output of Hippo signaling in cell competition

eLife ◽

10.7554/elife.38843 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 12

Author(s):

Pengfei Guo ◽

Chang-Hyun Lee ◽

Huiyan Lei ◽

Yonggang Zheng ◽

Katiuska Daniela Pulgar Prieto ◽

...

Keyword(s):

Dna Binding ◽

Hippo Pathway ◽

Ectopic Expression ◽

Tissue Growth ◽

Hippo Signaling ◽

Dependent Manner ◽

Cell Competition ◽

Regulatory Mode ◽

The Hippo Pathway ◽

Transcriptional Output

The Hippo tumor suppressor pathway regulates tissue growth in Drosophila by restricting the activity of the transcriptional coactivator Yorkie (Yki), which normally complexes with the TEF/TEAD family DNA-binding transcription factor Scalloped (Sd) to drive the expression of growth-promoting genes. Given its pivotal role as a central hub in mediating the transcriptional output of Hippo signaling, there is great interest in understanding the molecular regulation of the Sd-Yki complex. In this study, we identify Nerfin-1 as a transcriptional repressor that antagonizes the activity of the Sd-Yki complex by binding to the TEA DNA-binding domain of Sd. Consistent with its biochemical function, ectopic expression of Nerfin-1 results in tissue undergrowth in an Sd-dependent manner. Conversely, loss of Nerfin-1 enhances the ability of winner cells to eliminate loser cells in multiple scenarios of cell competition. We further show that INSM1, the mammalian ortholog of Nerfin-1, plays a conserved role in repressing the activity of the TEAD-YAP complex. These findings reveal a novel regulatory mode converging on the transcriptional output of the Hippo pathway that may be exploited for modulating the YAP oncoprotein in cancer and regenerative medicine.

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The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

Life Science Alliance ◽

10.26508/lsa.201900381 ◽

2019 ◽

Vol 2 (4) ◽

pp. e201900381 ◽

Cited By ~ 5

Author(s):

Stephan U Gerlach ◽

Moritz Sander ◽

Shilin Song ◽

Héctor Herranz

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Target Genes ◽

Hippo Pathway ◽

Growth Control ◽

Tissue Growth ◽

Tumor Formation ◽

Hippo Signaling ◽

Cell Cycle Regulators ◽

The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

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Activation mechanisms of the Hippo kinase signaling cascade

Bioscience Reports ◽

10.1042/bsr20171469 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 20

Author(s):

Sung Jun Bae ◽

Xuelian Luo

Keyword(s):

Hippo Pathway ◽

Adaptor Proteins ◽

Tissue Growth ◽

Fine Tuning ◽

Hippo Signaling ◽

Kinase Activation ◽

The Core ◽

Activation Mechanisms ◽

Kinase Cascade ◽

The Hippo Pathway

First discovered two decades ago through genetic screens in Drosophila, the Hippo pathway has been shown to be conserved in metazoans and controls organ size and tissue homeostasis through regulating the balance between cell proliferation and apoptosis. Dysregulation of the Hippo pathway leads to aberrant tissue growth and tumorigenesis. Extensive studies in Drosophila and mammals have identified the core components of Hippo signaling, which form a central kinase cascade to ultimately control gene expression. Here, we review recent structural, biochemical, and cellular studies that have revealed intricate phosphorylation-dependent mechanisms in regulating the formation and activation of the core kinase complex in the Hippo pathway. These studies have established the dimerization-mediated activation of the Hippo kinase (mammalian Ste20-like 1 and 2 (MST1/2) in mammals), the dynamic scaffolding and allosteric roles of adaptor proteins in downstream kinase activation, and the importance of multisite linker autophosphorylation by Hippo and MST1/2 in fine-tuning the signaling strength and robustness of the Hippo pathway. We highlight the gaps in our knowledge in this field that will require further mechanistic studies.

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Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

eLife ◽

10.7554/elife.08201 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 24

Author(s):

Sobhika Agarwala ◽

Sandra Duquesne ◽

Kun Liu ◽

Anton Boehm ◽

Lin Grimm ◽

...

Keyword(s):

Hippo Pathway ◽

Growth Control ◽

Tissue Growth ◽

Cell Junction ◽

Hippo Signaling ◽

Sensory Organs ◽

Hippo Signaling Pathway ◽

Tissue Size ◽

The Hippo Pathway ◽

First Time

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. In this study, we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.

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Impaired Hippo signaling promotes Rho1–JNK-dependent growth

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1415020112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1065-1070 ◽

Cited By ~ 23

Author(s):

Xianjue Ma ◽

Yujun Chen ◽

Wenyan Xu ◽

Nana Wu ◽

Maoquan Li ◽

...

Keyword(s):

Rho Gtpases ◽

Hippo Pathway ◽

Tissue Growth ◽

Hippo Signaling ◽

Jnk Pathway ◽

Jnk Signaling ◽

Dependent Growth ◽

Jnk Activation ◽

The Hippo Pathway

The Hippo and c-Jun N-terminal kinase (JNK) pathway both regulate growth and contribute to tumorigenesis when dysregulated. Whereas the Hippo pathway acts via the transcription coactivator Yki/YAP to regulate target gene expression, JNK signaling, triggered by various modulators including Rho GTPases, activates the transcription factors Jun and Fos. Here, we show that impaired Hippo signaling induces JNK activation through Rho1. Blocking Rho1–JNK signaling suppresses Yki-induced overgrowth in the wing disk, whereas ectopic Rho1 expression promotes tissue growth when apoptosis is prohibited. Furthermore, Yki directly regulates Rho1 transcription via the transcription factor Sd. Thus, our results have identified a novel molecular link between the Hippo and JNK pathways and implicated the essential role of the JNK pathway in Hippo signaling-related tumorigenesis.

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TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth

Journal of Experimental Medicine ◽

10.1084/jem.20111653 ◽

2012 ◽

Vol 209 (3) ◽

pp. 479-494 ◽

Cited By ~ 118

Author(s):

Makiko Fujii ◽

Takeshi Toyoda ◽

Hayao Nakanishi ◽

Yasushi Yatabe ◽

Ayuko Sato ◽

...

Keyword(s):

Malignant Mesothelioma ◽

Expression Patterns ◽

Hippo Pathway ◽

Neurofibromatosis Type ◽

Tissue Growth ◽

Hippo Signaling ◽

Downstream Signaling ◽

Matrix Deposition ◽

Tissue Specimens ◽

The Hippo Pathway

Malignant mesothelioma (MM) is an incurable malignancy that is caused by exposure to asbestos and is accompanied by severe fibrosis. Because MM is usually diagnosed at an advanced stage and clinical identification of early lesions is difficult, its molecular pathogenesis has not been completely elucidated. Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP). In this study, we demonstrate a functional interaction between the Hippo and TGF-β pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in MM cells was induced by the formation of a YAP–TEAD4–Smad3–p300 complex on the CTGF promoter. Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. We further suggest that CTGF may influence the malignancy of mesothelioma because of the different histological expression patterns observed in human MM tissues. These data suggest that CTGF is an important modulator of MM growth and pathology and represents a novel therapeutic target for this disease.

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Hippo Pathway in Regulating Drug Resistance of Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms222413431 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13431

Author(s):

Giacomo Casati ◽

Laura Giunti ◽

Anna Lisa Iorio ◽

Arianna Marturano ◽

Luisa Galli ◽

...

Keyword(s):

Hippo Pathway ◽

Binding Motif ◽

Hippo Signaling ◽

Pathway Activation ◽

Promising Target ◽

Kinase Cascade ◽

Tumor Immunosuppression ◽

The Central Nervous System ◽

Immunosuppressive Microenvironment ◽

The Hippo Pathway

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.

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Spectrin regulates Hippo signaling by modulating cortical actomyosin activity

eLife ◽

10.7554/elife.06567 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 58

Author(s):

Hua Deng ◽

Wei Wang ◽

Jianzhong Yu ◽

Yonggang Zheng ◽

Yun Qing ◽

...

Keyword(s):

Hippo Pathway ◽

Myosin Ii ◽

Tissue Growth ◽

Hippo Signaling ◽

Upstream Regulator ◽

Kinase Cascade ◽

Cytoskeletal Tension ◽

Living Tissues ◽

The Hippo Pathway ◽

Upstream Regulators

The Hippo pathway controls tissue growth through a core kinase cascade that impinges on the transcription of growth-regulatory genes. Understanding how this pathway is regulated in development remains a major challenge. Recent studies suggested that Hippo signaling can be modulated by cytoskeletal tension through a Rok-myosin II pathway. How cytoskeletal tension is regulated or its relationship to the other known upstream regulators of the Hippo pathway remains poorly defined. In this study, we identify spectrin, a contractile protein at the cytoskeleton-membrane interface, as an upstream regulator of the Hippo signaling pathway. We show that, in contrast to canonical upstream regulators such as Crumbs, Kibra, Expanded, and Merlin, spectrin regulates Hippo signaling in a distinct way by modulating cortical actomyosin activity through non-muscle myosin II. These results uncover an essential mediator of Hippo signaling by cytoskeleton tension, providing a new entry point to dissecting how mechanical signals regulate Hippo signaling in living tissues.

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