TheHippo signaling pathway, also known as theSalvador-Warts-Hippo (SWH)pathway, is asignaling pathway that controlsorgan size inanimals through the regulation ofcell proliferation andapoptosis. The pathway takes its name from one of its key signaling components—theprotein kinase Hippo (Hpo). Mutations in this gene lead totissue overgrowth, or a "hippopotamus"-likephenotype.

A fundamental question indevelopmental biology is how an organ knows to stop growing after reaching a particular size. Organ growth relies on several processes occurring at the cellular level, includingcell division andprogrammed cell death (or apoptosis). The Hippo signaling pathway is involved in restraining cell proliferation and promoting apoptosis. As many cancers are marked by unchecked cell division, this signaling pathway has become increasingly significant in the study of humancancer.^[1] The Hippo pathway also has a critical role in stem cell and tissue specific progenitor cell self-renewal and expansion.^[2]

The Hippo signaling pathway appears to behighly conserved. While most of the Hippo pathway components were identified in the fruit fly (Drosophila melanogaster) using mosaicgenetic screens,orthologs to these components (genes that are related through speciation events and thus tend to retain the same function in differentspecies) have subsequently been found inmammals. Thus, the delineation of the pathway inDrosophila has helped to identify many genes that function asoncogenes ortumor suppressors in mammals.

The Hippo pathway consists of a corekinase cascade in which Hpophosphorylates (Drosophila) the protein kinase Warts (Wts).^[3][4] Hpo (MST1/2 in mammals) is a member of the Ste-20 family of protein kinases. This highly conserved group ofserine/threonine kinases regulates several cellular processes, including cell proliferation, apoptosis, and various stress responses.^[5] Once phosphorylated, Wts (LATS1/2 in mammals) becomes active. Misshapen (Msn, MAP4K4/6/7 in mammals) and Happyhour (Hppy, MAP4K1/2/3/5 in mammals) act in parallel to Hpo to activate Wts.^[6][7][8] Wts is a nuclear DBF-2-related kinase. These kinases are known regulators of cell cycle progression, growth, and development.^[9] Two proteins are known to facilitate the activation of Wts: Salvador (Sav) and Mob as tumor suppressor (Mats). Sav (SAV1 in mammals) is aWW domain-containing protein, meaning that this protein contains a sequence ofamino acids in which atryptophan and an invariantproline are highly conserved.^[10] Hpo can bind to and phosphorylate Sav, which may function as ascaffold protein because this Hpo-Sav interaction promotes phosphorylation of Wts.^[11] Hpo can also phosphorylate and activate Mats (MOBKL1A/B in mammals), which allows Mats to associate with and strengthen the kinase activity of Wts.^[12]

Activated Wts can then go on to phosphorylate and inactivate thetranscriptional coactivator Yorkie (Yki). Yki is unable to bind DNA by itself. In its active state, Yki binds to the transcription factor Scalloped (Sd), and the Yki-Sd complex becomes localized to the nucleus. This allows for the expression of several genes that promote organ growth, such ascyclin E, which promotes cell cycle progression, anddiap1 (Drosophila inhibitor of apoptosis protein-1), which, as its name suggests, prevents apoptosis.^[13] Yki also activates expression of thebantammicroRNA, a positive growth regulator that specifically affects cell number.^[14][15] Thus, the inactivation of Yki by Wts inhibits growth through the transcriptional repression of these pro-growth regulators. By phosphorylating Yki at serine 168, Wts promotes the association of Yki with14-3-3 proteins, which help to anchor Yki in thecytoplasm and prevent its transport to the nucleus. In mammals, the two Yki orthologs are Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (WWTR1, also known as TAZ).^[16] When activated, YAP and TAZ can bind to several transcription factors includingp73,Runx2 and several TEADs.^[17] YAP regulates the expression of Hoxa1 and Hoxc13 in mouse and human epithelial cells in vivo and in vitro.^[18]

The upstream regulators of the core Hpo/Wts kinase cascade include thetransmembrane proteinFat and several membrane-associated proteins. As an atypicalcadherin, Fat (FAT1-4 in mammals) may function as a receptor, though an extracellularligand has not been positively identified. TheGPI-anchored cell surface protein glypican-3 (GPC3) is known to interact with Fat1 in human liver cancer.^[19] GPC3 is also shown to modulate Yap signaling in liver cancer.^[20] While Fat is known to bind to another atypical cadherin,Dachsous (Ds), during tissue patterning,^[21] it is unclear what role Ds has in regulating tissue growth. Nevertheless, Fat is recognized as an upstream regulator of the Hpo pathway. Fat activates Hpo through the apical protein Expanded (Ex; FRMD6/Willin in mammals). Ex interacts with two other apically-localized proteins, Kibra (KIBRA in mammals) andMerlin (Mer; NF2 in mammals), to form the Kibra-Ex-Mer (KEM) complex. Both Ex and Mer areFERM domain-containing proteins, while Kibra, like Sav, is a WW domain-containing protein.^[22] The KEM complex physically interacts with the Hpo kinase cascade, thereby localizing the core kinase cascade to the plasma membrane for activation.^[23] Fat may also regulate Wts independently of Ex/Hpo, through the inhibition of the unconventionalmyosin Dachs. Normally, Dachs can bind to and promote the degradation of Wts.^[24]

In fruitfly, the Hippo signaling pathway involves a kinase cascade involving the Salvador (Sav), Warts (Wts) and Hippo (Hpo)protein kinases.^[25] Many of the genes involved in the Hippo signaling pathway are recognized astumor suppressors, while Yki/YAP/TAZ is identified as anoncogene. YAP/TAZ can reprogram cancer cells intocancer stem cells.^[26] YAP has been found to be elevated in some human cancers, includingbreast cancer,colorectal cancer, andliver cancer.^[27][28][29] This may be explained by YAP's recently defined role in overcomingcontact inhibition, a fundamental growth control property of normal cellsin vitro andin vivo, in which proliferation stops after cells reachconfluence^[30] (in culture) or occupy maximum available space inside the body and touch one another. This property is typically lost in cancerous cells, allowing them to proliferate in an uncontrolled manner.^[31] In fact, YAP overexpression antagonizes contact inhibition.^[32]

Many of the pathway components recognized as tumor suppressor genes are mutated in human cancers. For example, mutations in Fat4 have been found in breast cancer,^[33] while NF2 is mutated in familial and sporadicschwannomas.^[34] Additionally, several human cancer cell lines invoke mutations of the SAV1 and MOBK1B proteins.^[35][36] However, recent research byMarc Kirschner and Taran Gujral has demonstrated that Hippo pathway components may play a more nuanced role in cancer than previously thought. Hippo pathway inactivation enhanced the effect of 15 FDA-approved oncology drugs by promoting chemo-retention.^[37] In another study, the Hippo pathway kinases LATS1/2 were found to suppress cancer immunity in mice.^[38] Not all studies, however, support a role for Hippo signaling in promoting carcinogenesis. Inhepatocellular carcinoma, for instance, it was suggesting thatAXIN1 mutations would provoke Hippo signaling pathway activation, fostering the cancer development, but a recent study demonstrated that such an effect cannot be detected.^[39] Thus the exact role of Hippo signaling in the cancer process awaits further elucidation.

Two venture-backed oncology startups, Vivace Therapeutics and the General Biotechnologies subsidiary Nivien Therapeutics, are actively developingkinase inhibitors targeting the Hippo pathway.^[40]

The heart is the first organ formed during mammalian development. A properly sized and functional heart is vital throughout the entire lifespan. Loss of cardiomyocytes because of injury or diseases leads to heart failure, which is a major cause of human morbidity and mortality. Unfortunately, regenerative potential of the adult heart is limited. The Hippo pathway is a recently identified signaling cascade that plays an evolutionarily conserved role in organ size control by inhibiting cell proliferation, promoting apoptosis, regulating fates of stem/progenitor cells, and in some circumstances, limiting cell size. Research indicates a key role of this pathway in regulation ofcardiomyocyte proliferation and heart size. Inactivation of the Hippo pathway or activation of its downstream effector, the Yes-associated protein transcription coactivator, improves cardiac regeneration. Several known upstream signals of the Hippo pathway such as mechanical stress, G-protein-coupled receptor signaling, andoxidative stress are known to play critical roles in cardiac physiology. In addition, Yes-associated protein has been shown to regulate cardiomyocyte fate through multiple transcriptional mechanisms.^[41][42][43]

Note that Hippo TAZ protein is often confused with the gene TAZ, which is unrelated to the Hippo pathway. The gene TAZ produces the protein tafazzin. The official gene name for the Hippo TAZ protein is WWTR1. Also, the official names for MST1 and MST2 are STK4 and STK3, respectively. All databases for bioinformatics use the official gene symbols, and commercial sources forPCR primers orsiRNA also go by the official gene names.

• Signal transduction
• Animal genes

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