WWTR1, also known as TAZ, is a protein encoded by the WWTR1 gene found within human cells. It significantly influences cell behavior, impacting processes like growth, division, and programmed cell death. Its proper function is important for maintaining cellular balance and tissue health.
The Role of WWTR1 in the Cell
WWTR1 functions as a transcriptional coactivator, working alongside transcription factors to regulate gene expression. It does not directly bind to DNA but assists transcription factors in promoting or suppressing specific gene activity. This regulatory role allows WWTR1 to influence a wide array of cellular processes.
WWTR1 primarily influences cell growth, dictating how cells increase in size. It also impacts cell proliferation, the process of cell division. By controlling genes involved in the cell cycle, WWTR1 can encourage or restrict the rate at which cells multiply. This balance is important for normal tissue development and repair.
WWTR1 also plays a part in apoptosis, the body’s method of programmed cell death to remove old or damaged cells. By influencing genes that promote or inhibit apoptosis, WWTR1 helps ensure that unneeded or potentially harmful cells are eliminated efficiently. This control over cell fate prevents uncontrolled cell accumulation.
WWTR1’s involvement extends to mesenchymal stem cell differentiation, guiding these versatile cells to develop into specialized cell types like bone cells (osteoblasts) or fat cells (adipocytes). It promotes osteoblast differentiation by enhancing the activity of the transcription factor RUNX2, while simultaneously inhibiting adipocyte differentiation.
Regulation by the Hippo Pathway
WWTR1’s activity is tightly controlled by the Hippo signaling pathway, a network of proteins that regulates organ size and tissue regeneration. The Hippo pathway functions as a cellular “brake” on WWTR1, determining its activity level and influence on gene expression. This pathway ensures tissues grow to the correct size and damaged tissues can properly repair themselves.
The core of the Hippo pathway involves a cascade of protein kinases, enzymes that add phosphate groups to other proteins. MST1/2 and LATS1/2 kinases are central to this regulation. When the Hippo pathway is active, LATS1/2 phosphorylates WWTR1 at specific sites. This phosphorylation signals WWTR1 to be retained in the cytoplasm, where it cannot access the genes it regulates.
Phosphorylation also marks WWTR1 for degradation, meaning the protein is broken down and removed from the cell. This occurs through ubiquitylation, where a ubiquitin tag is attached to WWTR1, signaling its destruction by the proteasome. This tight control over WWTR1’s location and stability ensures its effects on gene expression are only exerted when appropriate.
Conversely, when the Hippo pathway is less active, WWTR1 is not extensively phosphorylated, allowing it to move into the nucleus. Once in the nucleus, WWTR1 binds to transcription factors, such as the TEAD family, to activate target genes involved in cell proliferation and survival. This dynamic regulation by the Hippo pathway manages cell growth and regeneration.
WWTR1’s Involvement in Health and Disease
Dysregulation of WWTR1, meaning it does not function correctly, has important implications for human health. When WWTR1 is overactive or present in abnormally high levels, it contributes to the development and progression of various diseases, particularly cancers. Its altered activity can promote uncontrolled cell growth and division, hallmarks of cancer.
WWTR1 is implicated in several types of cancer, including breast cancer, colon cancer, lung cancer, and melanoma. In these malignancies, elevated WWTR1 levels can drive tumor growth, increase the ability of cancer cells to spread (metastasis), and lead to resistance to certain chemotherapy drugs. For example, in breast cancer, overexpression of WWTR1 can enhance cell migration and invasion.
Beyond cancer, WWTR1 also plays roles in normal developmental processes. It is involved in organ formation and tissue repair after injury. For example, WWTR1 is expressed in thyroid tissues and interacts with transcription factors important for thyroid development. Proper WWTR1 function is also connected to kidney and lung development, and a lack of WWTR1 can lead to conditions like polycystic kidney disease and emphysema.
Given its widespread involvement in both healthy cellular processes and disease, WWTR1 is being explored as a potential target for therapeutic interventions. Strategies aimed at inhibiting its overactivity or restoring its proper regulation could offer new avenues for treating diseases where WWTR1 dysregulation is a contributing factor. Researchers are investigating ways to disrupt WWTR1’s interactions with its binding partners or to promote its degradation to counteract its disease-promoting effects.