Yes-associated protein (YAP) is a protein that helps control which genes in a cell are turned on or off. It acts as a transcriptional coactivator, meaning it does not bind to DNA directly but partners with DNA-binding proteins from the TEAD family to manage gene expression. The genes influenced by YAP are fundamental to cellular activities, including how cells grow, multiply, and organize into tissues.
These processes are integral for determining organ size and facilitating tissue repair. When active, YAP promotes cell proliferation and helps cells avoid programmed death, also known as apoptosis. This regulation ensures that tissue growth happens in a controlled manner.
The Hippo Signaling Pathway as the Master Regulator
The activity of YAP is primarily controlled by the Hippo signaling pathway, which acts as an “off switch.” This pathway is sensitive to the physical state of cells, particularly how tightly they are packed together. When cells are dense and have extensive contact with their neighbors, a state known as contact inhibition, the Hippo pathway becomes active.
An active Hippo pathway uses kinases named LATS1/2 to add a phosphate group to YAP, a process called phosphorylation. This chemical tag traps YAP in the cell’s cytoplasm. By being held in the cytoplasm, YAP is prevented from reaching the cell’s nucleus, where the gene-activation machinery is located.
Conversely, when cells are sparse or receive certain mechanical signals, the Hippo pathway is inactive. In this state, YAP is not phosphorylated and is free to travel into the nucleus, where it activates its target genes. This regulation ensures that YAP’s growth-promoting functions are used only when needed for tissue growth or repair.
The shuttling of YAP between the cytoplasm and nucleus allows cells to respond to their local environment. This regulation is fundamental for maintaining tissue structure and size.
Core Functions of YAP Target Genes
The genes activated by YAP perform necessary physiological roles for tissue development and maintenance. These target genes can be grouped by their primary functions, which ensure that tissues grow to the correct size and can repair themselves.
A primary function of YAP target genes is to promote cell proliferation and survival. Two well-documented target genes in this category are CTGF (Connective Tissue Growth Factor) and CYR61. When activated, these genes produce proteins that are secreted to signal neighboring cells to divide and grow, and they also produce signals that inhibit apoptosis. The proteins from genes like CTGF and CYR61 are part of a communication network between cells that sustains tissue health.
The YAP pathway also acts as a sensor for organ size. As an organ grows and its cells become more densely packed, the Hippo pathway is activated, which in turn switches YAP off. This feedback loop stops the expression of pro-growth genes and halts further expansion once the organ has reached its genetically predetermined size. This mechanism ensures that organs like the liver or heart do not grow uncontrollably.
YAP target genes are also involved in maintaining populations of stem cells. YAP activity helps sustain these unspecialized cells until they are needed for tissue repair. When an injury occurs, YAP can become activated in the area, prompting stem cells to differentiate into the specific cell types required to mend the damage.
Consequences of YAP Dysregulation in Disease
When the regulation of the Hippo-YAP pathway breaks down, the system can become stuck in an “on” state. This causes YAP to continuously enter the nucleus and activate its target genes, leading to uncontrolled cellular behavior that can drive disease. The constant expression of genes that promote growth and block cell death is a factor in several pathological conditions.
Cancer is a prominent example of what happens when YAP is perpetually active. In many types of cancer, including those of the liver, lung, and colon, the Hippo pathway is often faulty or inactivated. This allows YAP to accumulate in the nucleus, where it drives the expression of its pro-growth and anti-apoptosis target genes. The result is the formation and progression of tumors, as cells divide without restraint.
The overactivity of YAP provides cancer cells an advantage, allowing them to proliferate rapidly and resist death signals. This makes hyperactive YAP a contributor to the aggressiveness and survival of many tumors.
Beyond cancer, excessive YAP activity is a driver of fibrosis, a condition characterized by the hardening or scarring of tissue. In organs like the heart, lungs, or liver, chronic injury can lead to sustained YAP activation. This causes an over-activation of target genes like CTGF, which stimulates cells to deposit excessive amounts of collagen. This buildup of scar tissue can impair organ function and ultimately lead to organ failure.
Therapeutic Targeting of the YAP Pathway
Due to the link between YAP overactivity and diseases like cancer and fibrosis, researchers are developing therapies to correct this dysregulation. The goal of these therapies is to interrupt the pathway at various points to restore normal cellular control. These approaches aim to either reduce the amount of active YAP or block the effects of its target genes.
One strategy involves preventing YAP from entering the nucleus. Since YAP must be in the nucleus to function, drugs that can force it to remain in the cytoplasm would effectively turn it off. Researchers are exploring small molecules that could mimic the effect of the Hippo pathway, promoting the phosphorylation of YAP and trapping it outside the nucleus.
Another approach focuses on disrupting the connection between YAP and its partner proteins, the TEAD transcription factors. Developing drugs that block the binding site between YAP and TEAD would prevent the activation of growth-promoting genes, even if YAP successfully enters the nucleus.
A third strategy involves directly targeting the protein products of YAP target genes. For example, since the CTGF gene is a driver of fibrosis, antibodies and other molecules have been developed to neutralize the CTGF protein itself. This approach does not correct the YAP overactivity but instead mitigates its downstream consequences by blocking the harmful signals produced by the target genes.