Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing. [5]
Hepatocyte growth factor regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the proto-oncogenic c-Met receptor. [6] [7] Hepatocyte growth factor is secreted by platelets, [8] and mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. Its ability to stimulate mitogenesis, cell motility, and matrix invasion gives it a central role in angiogenesis, tumorogenesis, and tissue regeneration. [9]
It is secreted as a single inactive polypeptide and is cleaved by serine proteases into a 69-kDa alpha-chain and 34-kDa beta-chain. A disulfide bond between the alpha and beta chains produces the active, heterodimeric molecule. The protein belongs to the plasminogen subfamily of S1 peptidases but has no detectable protease activity. [9]
Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction. [10] [11] As well as the well-characterised effects of HGF on epithelial cells, endothelial cells and haemopoietic progenitor cells, HGF also regulates the chemotaxis of T cells into heart tissue. Binding of HGF by c-Met, expressed on T cells, causes the upregulation of c-Met, CXCR3, and CCR4 which in turn imbues them with the ability to migrate into heart tissue. [12] HGF also promotes angiogenesis in ischemia injury. [13] HGF may further play a role as an indicator for prognosis of chronicity for Chikungunya virus induced arthralgia. High HGF levels correlate with high rates of recovery. [14]
Excessive local expression of HGF in the breasts has been implicated in macromastia. [15] HGF is also importantly involved in normal mammary gland development. [16] [17]
HGF has been implicated in a variety of cancers, including of the lungs, pancreas, thyroid, colon, and breast. [18] [19] [20]
Increased expression of HGF has been associated with the enhanced and scarless wound healing capabilities of fibroblast cells isolated from the oral mucosa tissue. [21]
Plasma from patients with advanced heart failure presents increased levels of HGF, which correlates with a negative prognosis and a high risk of mortality. [22] [23] Circulating HGF has been also identified as a prognostic marker of severity in patients with hypertension. [24] Circulating HGF has been also suggested as a precocious biomarker for the acute phase of bowel inflammation. [25]
Exogenous HGF administered by intravenous injection is cleared rapidly from circulation by the liver, with a half-life of approximately 4 minutes. [26] [27] [28] [29]
Dihexa is an orally active, centrally penetrant small-molecule compound that directly binds to HGF and potentiates its ability to activate its receptor, c-Met. [30] It is a strong inducer of neurogenesis and is being studied for the potential treatment of Alzheimer's disease and Parkinson's disease. [31] [32]
Hepatocyte growth factor has been shown to interact with the protein product of the c-Met oncogene, identified as the HGF receptor (HGFR). [6] [33] [34] Both overexpression of the Met/HGFR receptor protein and autocrine activation of Met/HGFR by simultaneous expression of the hepatocyte growth factor ligand have been implicated in oncogenesis. [35] [36] Hepatocyte growth factor interacts with the sulfated glycosaminoglycans heparan sulfate and dermatan sulfate. [37] [38] The interaction with heparan sulfate allows hepatocyte growth factor to form a complex with c-Met that is able to transduce intracellular signals leading to cell division and cell migration. [37] [39]
Morphogenesis is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of tissue growth and patterning of cellular differentiation.
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word mamma, "breast". The mammary glands are arranged in organs such as the breasts in primates, the udder in ruminants, and the dugs of other animals. Lactorrhea, the occasional production of milk by the glands, can occur in any mammal, but in most mammals, lactation, the production of enough milk for nursing, occurs only in phenotypic females who have gestated in recent months or years. It is directed by hormonal guidance from sex steroids. In a few mammalian species, male lactation can occur. With humans, male lactation can occur only under specific circumstances.
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Hepatocyte growth factor receptor is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.
Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.
Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.
Neuromedin U is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.
Syndecan-2 is a protein that in humans is encoded by the SDC2 gene.
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.
Keratinocyte growth factor is a protein that in humans is encoded by the FGF7 gene.
Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.
Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.
Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life.
c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase, the receptor of hepatocyte growth factor/scatter factor (HGF/SF). These inhibitors may have therapeutic application in the treatment of various types of cancers.
Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease, as well as treatment for the damage that occurs to the heart after MI. After MI, the myocardium suffers from reperfusion injury which leads to death of cardiomyocytes and detrimental remodelling of the heart, consequently reducing proper cardiac function. Transfection of cardiac myocytes with human HGF reduces ischemic reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI.
Madin-Darby canine kidney (MDCK) cells are a model mammalian cell line used in biomedical research. MDCK cells are used for a wide variety of cell biology studies including cell polarity, cell-cell adhesions, collective cell motility, toxicity studies, as well as responses to growth factors. It is one of few cell culture models that is suited for 3D cell culture and multicellular rearrangements known as branching morphogenesis.
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