The Hippo pathway is a fundamental communication network within cells that governs their behavior and interaction. This system acts as an internal “stop-and-go” signal, regulating cell proliferation (cell division) and programmed cell death. It ensures tissues and organs achieve and maintain their appropriate dimensions, contributing to an organism’s precise development and structure. Understanding this system provides insights into the delicate balance required for healthy growth and function.
Key Proteins in the Hippo Pathway
The Hippo pathway involves several protein groups working together. Upstream signals, such as cell-to-cell contact or mechanical forces, initiate the process by influencing the activity of the pathway’s central component, the kinase cassette.
The kinase cassette includes specific protein kinases: mammalian STE20-like protein kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2 (LATS1/2). Scaffolding proteins like Salvador homologue 1 (SAV1) and Mps One Binder kinase activator proteins (MOB1) aid these kinases. A kinase adds a phosphate group to other proteins, altering their activity or location.
The pathway’s main effectors are two transcriptional co-activators, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). These proteins partner with others to influence gene expression. The pathway’s core function controls the cellular location and activity of YAP and TAZ.
How the Pathway Signals
The Hippo pathway uses “ON” and “OFF” signaling to regulate cell growth. When cells are densely packed, such as in a mature tissue, the pathway is “ON.” In this state, the kinase cassette (MST1/2 and LATS1/2) becomes active.
These active kinases add phosphate tags to YAP and TAZ proteins. This phosphorylation locks YAP and TAZ in the cytoplasm, preventing them from entering the nucleus. By keeping these growth-promoting proteins out of the nucleus, the “stop signal” is effectively delivered, inhibiting cell division and promoting processes that limit cell numbers.
Conversely, when space is available for growth, like during development or tissue repair, the Hippo pathway is “OFF,” promoting cell proliferation. The kinase cassette is largely inactive, so YAP and TAZ remain untagged. Without the restraining phosphate tag, YAP and TAZ move into the cell nucleus. There, they associate with transcription factors, such as the TEA domain (TEAD) family proteins, to activate genes that promote cell division, enhance cell survival, and contribute to tissue expansion.
Controlling Organ Size and Cell Growth
A primary function of the Hippo pathway is its role as a biological ruler, ensuring that organs do not grow beyond their predetermined size. This pathway calibrates cell proliferation and programmed cell death to maintain tissue homeostasis. As an organ develops and its cells become more crowded, increasing cell-to-cell contact activates the Hippo pathway.
When activated, the “Pathway ON” state restricts further growth by limiting the activity of growth-promoting proteins. This mechanism ensures that once an organ reaches its genetically defined dimensions, cell division slows, and excess cells are removed, preventing overgrowth. This control is important for proper development and sustained tissue function.
The pathway also regulates stem cells and facilitates tissue repair. During injury or when new cells are needed, the Hippo pathway must be temporarily turned “OFF” to allow for cell proliferation and differentiation. This transient activation enables the regeneration of damaged tissues and the replenishment of cell populations, demonstrating the pathway’s dynamic control.
The Link to Cancer and Other Diseases
Malfunctions within the Hippo pathway can have significant consequences for cellular control, often contributing to disease development. If components of the Hippo pathway are mutated or inactivated, the “stop signal” can no longer be effectively sent. This disruption leaves the downstream proteins, YAP and TAZ, permanently in an “ON” state for cell growth.
When YAP and TAZ are continuously active, they persistently enter the cell nucleus and drive the transcription of genes that promote uncontrolled cell proliferation and inhibit cell death. This unchecked growth is a hallmark of cancer, where cells divide without proper regulation. Defects in the Hippo pathway are commonly observed in various human cancers, including liver cancer, lung cancer, and colorectal cancer.
Beyond cancer, the Hippo pathway’s role in other conditions highlights its broad influence on cellular health. Dysregulation of this pathway has been implicated in the development of fibrosis, a condition characterized by excessive scarring of tissues, such as in the liver or lungs. Imbalances in Hippo signaling are also being investigated for their contribution to heart disease, where precise control of cell growth and repair is important for organ function.