Yes-associated protein (YAP) is a transcriptional co-activator that regulates gene expression. It functions primarily to relay signals from the cell’s external environment and physical state directly to the nucleus, determining whether a cell should grow and divide or remain quiescent. When active, YAP partners with DNA-binding proteins to switch on specific genetic programs that drive cellular expansion and survival, governing fundamental biological outcomes like tissue growth and repair.
How the Hippo Pathway Controls YAP Activity
The activity of YAP is tightly governed by the Hippo pathway, a signaling cascade that senses mechanical and cellular cues such as cell density. The core of this pathway is a kinase module that functions to phosphorylate and inactivate YAP. When cells are crowded or in close contact, MST1/2 kinases initiate phosphorylation events, activating the LATS1/2 kinases.
The activated LATS1/2 kinases then directly phosphorylate YAP at multiple sites, most notably at Serine 127. This phosphorylation causes YAP to bind to scaffolding proteins like 14-3-3, sequestering it within the cytoplasm. Once trapped, YAP cannot enter the nucleus to activate its target genes and is often marked for degradation.
Conversely, when cells are sparse or a tissue needs to grow, the Hippo kinase cascade is suppressed. This allows YAP to remain unphosphorylated and free to translocate into the cell nucleus. Nuclear YAP binds to its primary partners to initiate gene transcription. The subcellular localization of YAP (cytoplasmic/inactive versus nuclear/active) is the central mechanism controlling cell fate.
The Major Categories of YAP Target Genes
Once YAP translocates into the nucleus, it acts as a co-activator, significantly boosting the function of sequence-specific transcription factors. The most common and extensively studied DNA-binding partners for YAP are the Transcriptional Enhanced Associate Domain (TEAD) family of transcription factors. The YAP-TEAD complex then targets specific promoters to activate a genetic program categorized by distinct cellular functions.
This program includes genes that promote robust cell proliferation, pushing the cell through the division cycle. Specific targets include the oncogene MYC and cell cycle regulators like CCND1 (Cyclin D1) and FOXM1. Active YAP ensures the sustained and rapid division necessary for growth or regeneration.
Another major category involves genes that inhibit programmed cell death (apoptosis), promoting cell survival. YAP target genes contribute to the evasion of cell death, ensuring proliferating cells remain viable and resistant to stress signals. This anti-apoptotic function is particularly relevant in pathological conditions where cells gain an abnormal survival advantage.
Active YAP also drives a program that facilitates cell migration and invasiveness, often through the induction of the Epithelial-Mesenchymal Transition (EMT). Genes like AXL are activated, alongside EMT transcription factors such as TWIST1, SNAIL, and ZEB1. This activation allows cells to lose stable epithelial characteristics, gain a motile mesenchymal phenotype, and degrade the surrounding tissue matrix.
Finally, YAP targets genes involved in extracellular matrix (ECM) remodeling, which profoundly alters the structural environment of the tissue. Matricellular proteins like CTGF (Connective Tissue Growth Factor) and CYR61 (Cysteine-rich angiogenic protein 61) are upregulated. These factors regulate cell adhesion, migration, and the deposition of structural proteins, including FN1 (Fibronectin) and COL1A1 (Collagen I).
Regulating Organ Size and Tissue Repair
In a healthy organism, the activation of YAP target genes is a tightly controlled, temporary response essential for maintaining tissue homeostasis and facilitating repair. YAP acts as a physiological sensor of tissue damage or loss, triggering a regenerative response. Its activity is quickly ramped up following injury, allowing cells to divide until the original tissue mass is restored, at which point the Hippo pathway reactivates to suppress YAP.
A classic example of this controlled activation is the liver’s ability to regenerate after partial removal. The immediate loss of tissue mass suppresses the Hippo pathway, leading to the nuclear accumulation of YAP. Nuclear YAP drives the proliferation of hepatocytes by activating its target genes until the liver returns to its proper size and the density-sensing mechanisms shut down the signal.
In wound healing, the temporary activation of YAP target genes is crucial for closing the damaged area. Factors like CTGF and CYR61 are transiently expressed in fibroblasts and keratinocytes at the wound site. These proteins promote the migration of skin cells and the temporary laying down of new matrix material to bridge the gap before the tissue matures and the YAP signal is silenced.
YAP Overactivation in Disease
When the regulatory mechanisms of the Hippo pathway fail, persistent and uncontrolled activation of YAP target genes leads to various pathological conditions. The primary consequence of chronic YAP nuclear accumulation is oncogenesis, as the cell’s growth and survival program is permanently switched “on.” This sustained activation of proliferation-promoting genes like MYC and CCND1 leads to uncontrolled cell division, a hallmark of cancer.
Furthermore, the permanent expression of anti-apoptotic YAP targets allows cancer cells to resist therapeutic agents and evade immune surveillance. The activation of EMT-related target genes like TWIST1 and SNAIL enables cancer cells to become motile and invasive. This process facilitates metastasis, allowing cells to break away from the primary tumor, travel through the bloodstream, and colonize distant organs.
Beyond cancer, chronic YAP activation drives organ fibrosis, the excessive formation of scar tissue that impairs function in organs like the liver, lung, and heart. YAP drives fibroblasts to differentiate into contractile myofibroblasts. These cells permanently express high levels of matrix-remodeling genes, including ACTA2 (alpha-smooth muscle actin) and LOX, leading to the excessive deposition of a stiff, fibrous matrix.
Research efforts focus on therapeutically targeting the YAP-TEAD interaction to treat these diseases. Small molecules, such as the drug Verteporfin, disrupt the binding between YAP and TEAD, effectively silencing the pathological genetic program. By inhibiting this interaction, the goal is to selectively turn off the downstream target genes that fuel uncontrolled growth and fibrosis.