GO:0035329 hippo signaling: Genes, Functions & Research

The hippo signaling pathway (GO:0035329) is an evolutionarily conserved intracellular kinase cascade that controls organ size, cell fate, and tissue homeostasis [1,6]. It was initially discovered in Drosophila melanogaster through genetic screens for genes controlling tissue overgrowth, and its core architecture has been conserved throughout metazoans. In mammals, the pathway is initiated by the activation of the STE20-family kinases STK4 (MST1) and STK3 (MST2), which, together with the scaffold protein SAV1, phosphorylate and activate the NDR-family kinases LATS1 and LATS2 [1,6]. Activated LATS1/2, in complex with MOB1A/MOB1B, in turn phosphorylate the transcriptional co-activators YAP1 and WWTR1 (TAZ), promoting their cytoplasmic retention via 14-3-3 binding and/or ubiquitin-mediated degradation. When the cascade is inactive, YAP1/TAZ translocate to the nucleus and partner with TEAD family transcription factors to drive expression of proliferative and anti-apoptotic gene programs [1,6]. Because of its central role in growth control, hippo signaling is a major focus in cancer biology, regenerative medicine, and developmental biology [1,4,7]. Loss of hippo pathway components or hyperactivation of YAP1/TAZ leads to uncontrolled proliferation and is observed in numerous malignancies, including gliomas, pancreatic cancer, and other solid tumors [4,7,8]. Conversely, transient activation of YAP1/TAZ promotes tissue regeneration and stem cell expansion, making the pathway an attractive target for regenerative therapies [1,3]. The pathway also intersects with mechanotransduction, cell polarity, G-protein-coupled receptor signaling, and metabolic cues, positioning it as a signaling hub [1,6]. For researchers, GO:0035329 provides a standardized framework for annotating genes and processes related to this cascade. Understanding its molecular logic is essential for designing experiments that interrogate its role in development, disease, and therapeutic resistance [1,7]. This article summarizes the definition, mechanism, key genes, disease links, and research methods for hippo signaling, with a focus on how CRISPR-based models can accelerate discovery.

According to the Gene Ontology, hippo signaling (GO:0035329) is defined as an intracellular signaling cascade that starts with the activation of hippo (STK4/MST1 and STK3/MST2 in mammals and hpo kinase in Drosophila). Hippo then phosphorylates LATS1/2, which in turn phosphorylates the transcriptional co-activator YAP1 (yki in Drosophila), leading to its cytosolic retention and/or degradation. In simpler terms, it is a kinase relay that receives upstream signals and ultimately controls whether YAP1/TAZ can enter the nucleus to turn on growth-promoting genes.

Hippo signaling is critically important because it governs fundamental decisions about cell proliferation, survival, and differentiation, and its dysregulation is a driving force in many human diseases, especially cancer [1,7]. The pathway integrates diverse upstream cues, including mechanical forces, cell density, and metabolic status, to fine-tune YAP1/TAZ activity, making it a central node in tissue homeostasis and regeneration [1,6]. Its evolutionary conservation from Drosophila to mammals underscores its fundamental biological significance.

The following table lists key genes and proteins that constitute or regulate the hippo signaling pathway (GO:0035329), along with their major roles and relevance for research.

Hippo signaling is regulated at multiple levels. Upstream, cell-cell contact, apical-basal polarity, mechanical forces, and G-protein-coupled receptor signaling modulate the activity of STK3/STK4 and LATS1/2 [1,6]. For example, the NF2 tumor suppressor and the WWC1 (KIBRA) protein promote LATS1/2 activation in response to cell density. Post-translational modifications also play a key role: PRMT5-mediated methylation of STK3/MST2 inhibits hippo signaling and promotes pancreatic cancer progression. Additionally, phosphorylation, ubiquitination, and sumoylation of YAP1/TAZ fine-tune their stability and localization. Crosstalk with other pathways, such as Wnt and TGF-beta, further integrates hippo signaling into cellular decision-making networks.

Dysregulation of hippo signaling is a common feature of many human cancers. Loss-of-function mutations in core pathway components such as NF2, LATS1/2, or STK3/STK4, or amplification of YAP1/TAZ, lead to constitutive activation of YAP1/TAZ and uncontrolled cell proliferation [1,7]. In gliomas, aberrant hippo signaling contributes to tumorigenesis and malignant progression. In pancreatic cancer, PRMT5-mediated methylation of STK3/MST2 inhibits hippo signaling and promotes cancer progression, highlighting post-translational regulation as a therapeutic target. Furthermore, YAP1/TAZ activation has been linked to resistance to targeted therapies and chemotherapies in multiple cancer types.

Hippo signaling plays critical roles in mammalian reproduction, including regulation of endometrial function, embryo implantation, and placental development [2,5]. In the endometrium, the pathway controls cell proliferation and differentiation in response to hormonal cues, and its dysregulation has been associated with reproductive disorders. Studies in animal models have shown that conditional knockout of hippo pathway genes leads to fertility defects, underscoring its importance in reproductive biology.

Emerging evidence implicates hippo-YAP/TAZ signaling in musculoskeletal disorders, including osteoarthritis, osteoporosis, and muscle wasting. The pathway regulates the differentiation and proliferation of chondrocytes, osteoblasts, and myoblasts, and its modulation can promote tissue regeneration. In regenerative medicine, transient activation of YAP1/TAZ has been shown to enhance tissue repair in various organs, making it a promising target for therapeutic intervention [1,3].

RNA sequencing is widely used to profile gene expression changes upon modulation of hippo signaling. For example, comparing YAP1/TAZ knockout or overexpression cells to controls reveals the transcriptional programs driven by the pathway [1,6]. This approach can identify downstream targets and feedback regulators.

Mass spectrometry-based phosphoproteomics allows global identification of phosphorylation events mediated by STK3/STK4 and LATS1/2. This is particularly useful for mapping the kinase substrates and understanding how hippo signaling rewires cellular signaling networks.

Fluorescence microscopy of tagged YAP1 or TAZ (e.g., GFP fusion) is a standard method to assess their nuclear versus cytoplasmic localization, which is a direct readout of hippo pathway activity. Live-cell imaging can track dynamics in response to mechanical or chemical cues.

Pooled CRISPR knockout screens can identify genes that regulate hippo signaling or that are required for YAP1/TAZ-driven proliferation. Such screens have uncovered novel components and therapeutic targets in cancer models.

Researchers studying hippo signaling-related genes often need to determine whether a candidate gene is causally involved in pathway regulation or disease. CRISPR-based models provide a robust way to establish causality by precisely manipulating the genome. EDITGENE offers a comprehensive suite of services to support such studies.

Hippo signaling (GO:0035329) is a fundamental intracellular kinase cascade that controls cell proliferation, organ size, and tissue homeostasis, with profound implications for cancer, regeneration, and development [1,6]. Its core components, from STK3/STK4 to YAP1/TAZ, are highly conserved and extensively studied, yet many aspects of its regulation and crosstalk remain to be fully elucidated [1,7]. CRISPR-based models are indispensable for dissecting the causal roles of hippo pathway genes in health and disease. EDITGENE's comprehensive services empower researchers to generate precise genetic models and accelerate discoveries in this vital field.