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The balance between cell proliferation and death: How does the Hippo signaling pathway regulate a fundamental rule of life?
In the growth and development of animals, one signaling pathway plays a key role, and that is the Hippo signaling pathway. This signaling pathway not only controls organ size but also maintains the basic rules of life by regulating cell proliferation and apoptosis. The Hippo signaling pathway is named after one of its major signaling components, Hippo protein kinase (Hpo), whose mutations can lead to excessive tissue growth and a "hippo"-like phenotype.
How organs stop growing after reaching a certain size is a fundamental question in developmental biology.
Organ growth depends on multiple processes at the cellular level, including cell division and programmed death (i.e., apoptosis). The Hippo signaling pathway plays an important role in inhibiting cell proliferation and promoting apoptosis. As tumors are often characterized by uncontrolled cell division, the Hippo signaling pathway has become increasingly important in the study of human cancer. In addition, the Hippo signaling pathway also plays a crucial role in the self-renewal and expansion of stem cells and precursor cells of specific tissues.
A notable feature of the Hippo signaling pathway is its conservation. Although most of its components were first discovered in the fruit fly (Drosophila melanogaster), its homologous genes (genes that retain the same function in different species through the process of speciation) were also subsequently discovered in recognized in mammals. This allowed understanding of this pathway in Drosophila to help identify many genes that function as oncogenes or tumor suppressors in mammals.
Mechanism of Hippo signaling pathway
The Hippo signaling pathway consists of a core kinase cascade, in which Hpo plays a key role in the phosphorylation of the steady-state target protein Warts (Wts). In Drosophila, Hpo kinase belongs to the Ste-20 protein kinase family, which regulates a variety of cellular processes, including cell proliferation, apoptosis, and various stress responses.
Activated Wts phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki), thereby inhibiting cell proliferation.
Phosphorylated Wts (LATS1/2 in mammals) becomes active. Misshapen (Msn) and Happyhour (Hppy) are another group of proteins that act on Hpo, and they act in parallel with Hpo to activate Wts. Significantly, these kinases are generally considered regulators of cell cycle progression, growth, and development.
Hippo signaling pathway and cancer
In Drosophila, the kinase cascade involved in the Hippo signaling pathway is also considered a tumor suppressor, especially Yki/YAP/TAZ, which was identified as an oncogene. YAP/TAZ can reprogram cancer cells to transform into cancer stem cells. Currently, YAP expression has been found to be increased in certain types of human cancers, such as breast cancer, colorectal cancer, and liver cancer, which may be related to YAP's role in overcoming contact inhibition.
Contact inhibition is a basic growth control characteristic that causes normal cells to stop proliferating after reaching a saturated state in culture or in vivo.
As tumor cells often lose their contact-inhibitory properties, they are unable to undergo correct growth control and exhibit uncontrolled proliferation characteristics. It is worth noting that the roles of components of the Hippo pathway in cancer are not uniform. For example, inactivation of the Hippo pathway may enhance the effects of some FDA-approved anti-cancer drugs. In addition, some studies have pointed out that the Hippo pathway plays a role in suppressing cancer immunity in mice.
Hippo signaling pathway as a drug target
With a deeper understanding of the Hippo signaling pathway, more and more biotechnology companies are focusing on it as a potential target for drugs. Among them, Vivace Therapeutics and Nivien Therapeutics are actively developing kinase inhibitors targeting the Hippo pathway to develop new anti-cancer therapies.
Regulating human organ size
The heart is the earliest organ formed during the development of mammals. A heart of normal size and function is crucial to the entire life cycle of humans. However, the regenerative potential of the adult heart is limited, and studies of the Hippo pathway have shown its important role in the regulation of heart size. Activating the Yes-related protein transcriptional coactivator helps improve cardiac regeneration, a finding that provides new ideas for the treatment of heart diseases.
The Hippo pathway is also regulated by upstream signals such as mechanical stress and oxidative stress in cardiac physiology.
Excessive damage or disease to the heart can lead to the loss of cardiomyocytes, leading to heart failure, which is one of the important causes of human morbidity and mortality.
In the Hippo signaling pathway, the Hippo TAZ protein is often mistaken for the unrelated TAZ gene. The official name of the Hippo TAZ protein is WWTR1, while the official names of MST1 and MST2 are STK4 and STK3 respectively. Official gene symbols are used in bioinformatics databases, and commercial PCR primers or siRNA also use official names.
Research on the Hippo signaling pathway demonstrates the art of balance between proliferation and death. Under what circumstances do we need this balance, and how can we regulate this process?
