Hepsin is a serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL [, ].
This entry includes hepatocyte growth factor (HGF; also called scatter factor) and HGF-like proteins (also known as macrophage stimulatory protein, MST1). Hepatocyte growth factor (HGF) is an activating ligand of the Met receptor tyrosine kinase, whose activity is essential for normal tissue development and organ regeneration []. HGF is essential for placental, liver, and muscle development, whereas MST1 is not required for embryogenesis, fertility, or wound healing. Genes for HGF and its receptor, the Met tyrosine kinase, are close together on chromosome 7, so that polysomy of chromosome 7 may contribute to malignancy through overproduction of both molecules. MST1 and its receptor, the Ron tyrosine kinase, are close together on chromosome 3. HGF and MST1 are closely related to plasminogen, having similar domain architecture: signal sequence followed by a PAN (formerly apple) domain, four (rather than five) kringle domains, and a trypsin domain, which appears to lack any peptidase activity.
Hepatocyte growth factor (HGF) is an activating ligand of the tyrosine kinase receptor Met. It activates Met by binding and promoting its dimerisation. This activation has been linked to promoting the invasive growth of many tumour types []. HGF acts as growth factor for a broad spectrum of tissues and cell types and has no detectable protease activity [].Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39). A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information [].
Plasma kallikrein () and coagulation factor XI () are two related plasma serine proteases activated by factor XIIA and which share the same domain topology: an N-terminal region that contains four tandem repeats of about 90 amino acids and a C-terminal catalytic domain. The 90 amino-acid repeated domain contains 6 conserved cysteines. It has been shown [, ]that three disulfide bonds link the first and sixth, second and fifth, and third and fourth cysteines. The domain can be drawn in the shape of an apple and has been accordingly called the 'apple domain'.The apple domains of plasma prekallikrein are known to mediate its binding to high molecular weight kininogen [], the apple domains of factor XI bind to factor XIIa, platelets, kininogen, factor IX and heparin [].The apple domains display some sequence similarity with the N domain of plasminogen/hepatocyte growth factor (HGF) and to some nematode and protozoan proteins []. They all belong to the same domain superfamily that have been called the PAN module []. The N domain of hepatocyte growth factor binds to the c-Met receptor and to the heparin molecule. The structure of the PAN module of HGF has been solved. It contains a characteristic hairpin-loop structure stabilised by two disulfide bridges, Cys-1 and 6 are not conserved in HGF PAN modules [].Apart from the cysteines, there are a number of other conserved positions in the apple domain. This entry represents the PAN domain of the plasma kalllikrein/coagulation factor XI subgroup proteins.
In the human adult, FKBP-12, also known as FAP68 or FK506-binding protein, (protein product of the gene glomulin) is expressed at highlevels in skeletal muscle, heart, brain and kidney, and at low levels in smaller arteries and veins. The high expression of glomulin in murine vasculature suggests an important role in blood vessel development and/or maintenance, which is supported by the vascular phenotype seen in GVM patients with mutations in this gene []. It is a cytoplasmic protein, specifically bound by the non-phosphorylated form of the hepatocyte growth factor, HGF, receptor and is released upon HGF stimulation and receptor phosphorylation, suggesting a potential role for FKBP12 in linking HGF signaling to the regulation of protein synthesis []. FKBP12 is found to regulate Ca2+release from the sarcoplasmic reticulum (SR) by its action on the IP3 receptors (IP3Rs), which crucially regulate diverse cell signalling processes from reproduction to apoptosis, possibly via the kinase rapamycin (mTOR), that potentiates Ca2+ release from the IP3R in smooth muscle []. This entry also include the aberrant root formation protein 4 (At5g11030) from Arabidopsis. It is required for the initiation of lateral roots independent from auxin signaling [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the receptor tyrosine kinases for HGF (hepatocyte growth factor) and MSP (macrophage-stimulating protein) []. The HGF receptor functions in cell proliferation, scattering, morphogenesis and survival [, ].
