Hippo signaling pathway
Encyclopedia
The Hippo signaling pathway, also known as the Salvador/Warts/Hippo (SWH) pathway, controls organ
size in animals through the regulation of cell proliferation and apoptosis
. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue
overgrowth, or a “hippopotamus
”-like phenotype
.
A fundamental question in developmental 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, including cell division
and programmed 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 human cancer
.
The Hippo signaling pathway appears to be highly conserved. While most of the Hippo pathway components were identified in the fruit fly (Drosophila melanogaster
) using mosaic genetic screens
, orthologs to these components (genes that function analogously in different species
) have subsequently been found in mammals. Thus, the delineation of the pathway in Drosophila has helped to identify many genes that function as oncogenes or tumor suppressors in mammals.
cascade in which Hpo phosphorylates
the protein kinase Warts (Wts). Hpo (MST1/2 in mammals) is a member of the Ste-20 family of protein kinases. This highly conserved group of serine/threonine kinases regulates several cellular processes, including cell proliferation, apoptosis, and various stress responses. Once phosphorylated, Wts (LATS1/2 in mammals) becomes active. Wts is a nuclear DBF-2-related kinase. These kinases are known regulators of cell cycle progression, growth, and development. Two proteins are known to facilitate the activation of Wts: Salvador (Sav) and Mob as tumor suppressor (Mats). Sav (WW45 in mammals) is a WW domain-containing protein, meaning that this protein contains a sequence of amino acids in which a tryptophan
and an invariant proline
are highly conserved. Hpo can bind to and phosphorylate Sav, which may function as a scaffold protein
because this Hpo-Sav interaction promotes phosphorylation of Wts. Hpo can also phosphorylate and activate Mats (MOBKL1A/B in mammals), which allows Mats to associate with and strengthen the kinase activity of Wts.
Activated Wts can then go on to phosphorylate and inactivate the transcriptional 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 as cyclin E
, which promotes cell cycle progression, and diap1 (Drosophila inhibitor of apopotosis protein-1), which, as its name suggests, prevents apoptosis. Yki also activates expression of the bantam microRNA, a positive growth regulator that specifically affects cell number. 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 with 14-3-3 proteins, which help to anchor Yki in the cytoplasm
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 (TAZ). When activated, YAP and TAZ can bind to several transcription factors including p73
, Runx2
and several TEADs.
The upstream regulators of the core Hpo/Wts kinase cascade include the transmembrane protein
Fat
and several membrane-associated proteins. As an atypical cadherin
, Fat (FAT1-4 in mammals) may function as a receptor, though an extracellular ligand
has not been positively identified. While Fat is known to bind to another atypical cadherin, Dachsous (Ds), during tissue patterning, 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; FDM6 in mammals). Ex interacts with two other apically-localized proteins, Kibra (KIBRA in mammals) and Merlin (Mer; NF2 in mammals), to form the Kibra-Ex-Mer (KEM) complex. Both Ex and Mer are FERM domain
-containing proteins, while Kibra, like Sav, is a WW domain-containing protein. The KEM complex physically interacts with the Hpo kinase cascade, thereby localizing the core kinase cacade to the plasma membrane for activation. Fat may also regulate Wts independently of Ex/Hpo, through the inhibition of the unconventional myosin
Dachs. Normally, Dachs can bind to and promote the degradation of Wts.
, while Yki/YAP/TAZ is identified as an oncogene
. In fact, YAP has been found to be elevated in some human cancers, including breast cancer
, colorectal cancer
, and liver cancer
. This may be explained by YAP’s recently defined role in overcoming contact inhibition
, a fundamental growth control property of normal cells in culture in which proliferation stops after cells reach confluence
. This property is typically lost in cancerous cells, allowing them to proliferate in an uncontrolled manner. In fact, YAP overexpression antagonizes contact inhibition.
Many of the pathway components recognized as tumor suppressor genes are mutated in human cancers. For example, mutations in Fat4 have been identified found in breast cancer, while NF2 is mutated in familial and sporadic schwanomas. Additionally, several human cancer cell lines invoke mutations of the WW45 and MOBK1B proteins.
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
size in animals through the regulation of cell proliferation and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
overgrowth, or a “hippopotamus
Hippopotamus
The hippopotamus , or hippo, from the ancient Greek for "river horse" , is a large, mostly herbivorous mammal in sub-Saharan Africa, and one of only two extant species in the family Hippopotamidae After the elephant and rhinoceros, the hippopotamus is the third largest land mammal and the heaviest...
”-like phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
A fundamental question in developmental biology
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
is how an organ knows to stop growing after reaching a particular size. Organ growth relies on several processes occurring at the cellular level, including cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and programmed 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 human cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
The Hippo signaling pathway appears to be highly conserved. While most of the Hippo pathway components were identified in the fruit fly (Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
) using mosaic genetic screens
Genetic screen
A genetic screen is a procedure or test to identify and select individuals who possess a phenotype of interest. A genetic screen for new genes is often referred to as forward genetics as opposed to reverse genetics, the term for identifying mutant alleles in genes that are already known...
, orthologs to these components (genes that function analogously in different species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
) have subsequently been found in mammals. Thus, the delineation of the pathway in Drosophila has helped to identify many genes that function as oncogenes or tumor suppressors in mammals.
Mechanism
The Hippo pathway consists of a core kinaseKinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
cascade in which Hpo phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
the protein kinase Warts (Wts). Hpo (MST1/2 in mammals) is a member of the Ste-20 family of protein kinases. This highly conserved group of serine/threonine kinases regulates several cellular processes, including cell proliferation, apoptosis, and various stress responses. Once phosphorylated, Wts (LATS1/2 in mammals) becomes active. Wts is a nuclear DBF-2-related kinase. These kinases are known regulators of cell cycle progression, growth, and development. Two proteins are known to facilitate the activation of Wts: Salvador (Sav) and Mob as tumor suppressor (Mats). Sav (WW45 in mammals) is a WW domain-containing protein, meaning that this protein contains a sequence of amino acids in which a tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
and an invariant proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
are highly conserved. Hpo can bind to and phosphorylate Sav, which may function as a scaffold protein
Scaffold protein
In biology, scaffold proteins are crucial regulators of many key signaling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signaling pathway, tethering them into complexes...
because this Hpo-Sav interaction promotes phosphorylation of Wts. Hpo can also phosphorylate and activate Mats (MOBKL1A/B in mammals), which allows Mats to associate with and strengthen the kinase activity of Wts.
Activated Wts can then go on to phosphorylate and inactivate the transcriptional coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
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 as cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
, which promotes cell cycle progression, and diap1 (Drosophila inhibitor of apopotosis protein-1), which, as its name suggests, prevents apoptosis. Yki also activates expression of the bantam microRNA, a positive growth regulator that specifically affects cell number. 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 with 14-3-3 proteins, which help to anchor Yki in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
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 (TAZ). When activated, YAP and TAZ can bind to several transcription factors including p73
P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
, Runx2
Runx2
Runt-related transcription factor 2 also known as core-binding factor subunit alpha-1 is a protein that in humans is encoded by the RUNX2 gene RUNX2 is a key transcription factor associated with osteoblast differentiation....
and several TEADs.
The upstream regulators of the core Hpo/Wts kinase cascade include the transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
Fat
FAT (gene)
Protocadherin Fat 1 is a protein that in humans is encoded by the FAT1 gene.-Further reading:...
and several membrane-associated proteins. As an atypical cadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
, Fat (FAT1-4 in mammals) may function as a receptor, though an extracellular ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
has not been positively identified. While Fat is known to bind to another atypical cadherin, Dachsous (Ds), during tissue patterning, 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; FDM6 in mammals). Ex interacts with two other apically-localized proteins, Kibra (KIBRA in mammals) and Merlin (Mer; NF2 in mammals), to form the Kibra-Ex-Mer (KEM) complex. Both Ex and Mer are FERM domain
FERM domain
In molecular biology, the FERM domain is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton...
-containing proteins, while Kibra, like Sav, is a WW domain-containing protein. The KEM complex physically interacts with the Hpo kinase cascade, thereby localizing the core kinase cacade to the plasma membrane for activation. Fat may also regulate Wts independently of Ex/Hpo, through the inhibition of the unconventional myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
Dachs. Normally, Dachs can bind to and promote the degradation of Wts.
The Hippo Signaling Pathway in Cancer
Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressorsTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
, while Yki/YAP/TAZ is identified as an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. In fact, YAP has been found to be elevated in some human cancers, including breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, and liver cancer
Liver cancer
Liver tumors or hepatic tumors are tumors or growths on or in the liver . Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. These growths can be benign or malignant...
. This may be explained by YAP’s recently defined role in overcoming contact inhibition
Contact inhibition
Contact inhibition is the natural process of arresting cell growth when two or more cells come into contact with each other. Oncologists use this property to distinguish between normal and cancerous cells....
, a fundamental growth control property of normal cells in culture in which proliferation stops after cells reach confluence
Confluency
In cell culture biology, confluency is the term commonly used as a measure of the number of the cells in a cell culture dish or a flask, and refers to the coverage of the dish or the flask by the cells...
. This property is typically lost in cancerous cells, allowing them to proliferate in an uncontrolled manner. In fact, YAP overexpression antagonizes contact inhibition.
Many of the pathway components recognized as tumor suppressor genes are mutated in human cancers. For example, mutations in Fat4 have been identified found in breast cancer, while NF2 is mutated in familial and sporadic schwanomas. Additionally, several human cancer cell lines invoke mutations of the WW45 and MOBK1B proteins.
Summary Table
| Drosophila melanogaster | Human ortholog(s) | Protein Description & Role in Hippo Signaling Pathway |
|---|---|---|
| Dachsous (Ds) | DCHS1 DCHS1 Protein dachsous homolog 1, also known as protocadherin-16 or cadherin-19 or cadherin-25 or fibroblast cadherin-1 , is a protein that in humans is encoded by the DCHS1 gene.- Function :... , DCHS2 DCHS2 Protein dachsous homolog 2, also known as protocadherin-23 or cadherin-27 , is a protein that in humans is encoded by the DCHS2 gene.... |
Atypical cadherin that may act as a ligand for the Fat receptor |
| Fat (Ft) | FAT1 FAT (gene) Protocadherin Fat 1 is a protein that in humans is encoded by the FAT1 gene.-Further reading:... , FAT2, FAT3, FAT4 FAT4 Protocadherin Fat 4, also known as cadherin family member 14 or FAT tumor suppressor homolog 4 , is a protein that in humans is encoded by the FAT4 gene.FAT4 is associated with the Hippo signaling pathway.... (FATJ) |
Atypical cadherin that may act as a receptor for the Hippo pathway |
| Expanded (Ex) | FDM6 FRMD6 FERM domain-containing protein 6 is a protein that in humans is encoded by the FRMD6 gene.-Further reading:PMID:21666719... |
FERM domain-containing apical protein that associates with Kibra and Mer as an upstream regulator of the core kinase cascade |
| Dachs (Dachs) | Unconventional myosin that can bind Wts, promoting its degradation | |
| Kibra (Kibra) | WWC1 WWC1 Protein KIBRA also known as kidney and brain expressed protein or WW domain-containing protein 1 is a protein that in humans is encoded by the WWC1 gene.... |
WW domain-containing apical protein that associates with Ex and Mer as an upstream regulator of the core kinase cascade |
| Merlin (Mer) | NF2 | FERM domain-containing apical protein that associates with Ex and Kibra as an upstream regulator of the core kinase cascade |
| Hippo (Hpo) | MST1 MST1 Hepatocyte growth factor-like protein is a protein that in humans is encoded by the MST1 gene.-Further reading:... , MST2 |
Sterile-20-type kinase that phosphorylates and activates Wts |
| Salvador (Sav) | WW45 (SAV1 SAV1 Protein salvador homolog 1 is a protein that in humans is encoded by the SAV1 gene.-Further reading:... ) |
WW domain-containing protein that may act as a scaffold protein, facilitating Warts phosphorylation by Hippo |
| Warts (Wts) | LATS1 LATS1 Serine/threonine-protein kinase LATS1 is an enzyme that in humans is encoded by the LATS1 gene.It has been associated with the Hippo signaling pathway.-Interactions:LATS1 has been shown to interact with Zyxin and Cdk1.-Further reading:... , LATS2 LATS2 Serine/threonine-protein kinase LATS2 is an enzyme that in humans is encoded by the LATS2 gene.-Further reading:... |
Nuclear DBF-2-related kinase that phosphorylates and inactivates Yki |
| Mob as tumor suppressor (Mats) | MOBKL1A MOBKL1A Mps one binder kinase activator-like 1A, also known as Mob1 homolog 1A, is a protein that in humans is encoded by the MOBKL1A gene.- Function :... , MOBKL1B MOBKL1B Mps one binder kinase activator-like 1B is an enzyme that in humans is encoded by the MOBKL1B gene.-Further reading:... |
Kinase that associates with Wts to potentiate its catalytic activity |
| Yorkie (Yki) | YAP YAP Yet Another Previewer is the name of two different document previewing applications, one for DVI and one for PostScript.-PostScript:... , TAZ Tafazzin Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle. It is involved in the metabolism of cardiolipin.... |
Transcriptional coactivator that binds to Sd in its active, unphosphorylated form to activate expression of transcriptional targets that promote cell growth, cell proliferation, and prevent apoptosis |
| Scalloped (Sd) | TEAD1 TEAD1 Transcriptional enhancer factor TEF-1 is a protein that in humans is encoded by the TEAD1 gene.-Interactions:TEAD1 has been shown to interact with MEF2C, Serum response factor and MAX.-Further reading:... , TEAD2 TEAD2 Transcriptional enhancer factor TEF-4 also known as TEA domain family member 2 is a protein that in humans is encoded by the TEAD2 gene. TEAD-2 is a transcription factor.- Clinical significance :... , TEAD3 TEAD3 Transcriptional enhancer factor TEF-5 is a protein that in humans is encoded by the TEAD3 gene.-Further reading:-External links:... , TEAD4 TEAD4 Transcriptional enhancer factor TEF-3 is a protein that in humans is encoded by the TEAD4 gene.-Further reading:... |
Transcription factor that binds Yki to regulate target gene expression |