Hippo signaling pathway

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The Hippo signaling pathway regulates a number of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis. Originally discovered and studied in Drosophila melanogaster, the pathway is highly conserved across species, and equivalent genes and their protein products involved in the Hippo pathway can be found in mammals¹.

The pathway consists of a complex cascade of serine/threonine-protein kinases. Serine threonine kinase 3 (STK3) and STK4 (also known as MST1 and MST2) are the mammalian equivalent of the Drosophila Hpo protein^1,2. These kinases form a complex with the adaptor protein, salvador homolog 1 (SAV1) to phosphorylate and activate the effector protein, large tumor suppressor 1/2 (LATS1/2). MAP4K and TAOK kinases also act in parallel to phosphorylate LATS1/2³. Once activated, LATS1/2 binds MOB kinase activator 1A/B (MOB1A/B) and inhibits the transcription cofactors yes-associated protein (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ or WWTR1)⁵. Neurofibromin 2 (NF2), a tumor suppressor protein, also acts to inhibit YAP/TAZ activity by promoting the activation of the pathway⁴. When the Hippo pathway is ‘off’, the phosphorylated YAP/TAZ is retained in the cytoplasm and may also undergo proteolytic degradation⁵. When the Hippo pathway is ‘on’, the unphosphorylated YAP/TAZ moves into the nucleus and binds to transcription factors called TEA DNA-binding proteins (TEAD1–4). The YAP/TAZ-TEAD complex regulates proliferative and pro-survival genes¹.

Dysregulation of the Hippo pathway, resulting in an increase in YAP/TAZ activity, is associated with cancer, promoting hyperproliferation, cellular invasion, metastasis, and chemoresistance⁷.  

What to expect

The pathway poster explores the kinase cascade at the core of the mammalian Hippo pathway, including STK3/4 (MST1/2), LATS1/2, YAP, and TAZ. Discover how these proteins interact with other key components such as MAPK kinases and find relevant products to research these targets.

​References​​

1. Meng, Z., Moroishi, T. & Guan, K. Mechanisms of Hippo pathway regulation. Genes & Development 30, 1-17 (2016).
2. Ready, D. et al. Mapping the STK4/Hippo signaling network in prostate cancer cell. PLOS ONE 12, e0184590 (2017).
3. Zinatizadeh, M. et al. The Hippo Tumor Suppressor Pathway (YAP/TAZ/TEAD/MST/LATS) and EGFR-RAS-RAF-MEK in cancer metastasis. Genes & Diseases (2019). doi:10.1016/j.gendis.2019.11.003
4. Plouffe, S. et al. Characterization of Hippo Pathway Components by Gene Inactivation. Molecular Cell 64, 993-1008 (2016).
5. Pobbati, A. & Hong, W. A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy. Theranostics 10, 3622-3635 (2020).
6. Calses, P., Crawford, J., Lill, J. & Dey, A. Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities. Trends in Cancer 5, 297-307 (2019).
7. Shreberk‐Shaked, M. & Oren, M. New insights into YAP/TAZ nucleo‐cytoplasmic shuttling: new cancer therapeutic opportunities? Molecular Oncology 13, 1335-1341 (2019).