Clusterin, also known as complement-associated protein SP-40, Complement cytolysis inhibitor, Apolipoprotein J, Testosterone-repressed prostate message 2, Aging-associated gene 4 protein, CLU and APOJ, is a secreted protein which belongs to the clusterin family. Clusterin/Apolipoprotein J/Apo-J is an enigmatic glycoprotein with a nearly ubiquitous tissue distribution and an apparent involvement in biological processes ranging from mammary gland involution to neurodegeneration in Alzheimer's disease. Its major form, a heterodimer, is secreted and present in physiological fluids, but truncated forms targeted to the nucleus have also been identified. Clusterin/Apolipoprotein J/Apo-J is a widely distributed glycoprotein with a wide range of biologic properties. A prominent and defining feature of clusterin is its marked induction in such disease states as glomerulonephritis, cystic renal disease, renal tubular injury, neurodegenerative conditions, atherosclerosis, and myocardial infarction. Upregulation of clusterin mRNA and protein levels detected in diverse disease states and in in vitro systems have led to suggestions that it functions in membrane lipid recycling, in apoptotic cell death, and as a stress-induced secreted chaperone protein, amongst others.
Clusterin, also known as Apolipoprotein J, Sulfated Glycoprotein 2 (SGP-2), TRPM-2, and SP-40,40, is a secreted multifunctional protein that was named for its ability to induce cellular clustering. It binds a wide range of molecules and may function as a chaperone of misfolded extracellular proteins. It also participates in the control of cell proliferation, apoptosis, and carcinogenesis. Clusterin is predominantly expressed in adult testis, ovary, adrenal gland, liver, heart, and brain and in many epithelial tissues during embryonic development. Mouse Clusterin is synthesized as a precursor that contains two coiled coil domains, two nuclear localization signals (NLS), and one heparin binding domain. Intracellular cleavages of the precursor remove the signal peptide and generate comparably sized alpha and beta chains which are secreted as an 80 kDa N-glycosylated disulfide-linked heterodimer. Mature mouse Clusterin shares 77% and 93% amino acid sequence identity with an human and rat Clusterin, respectively. High μg/mL concentrations of Clusterin circulate predominantly as a component of high density lipoprotein particles, and these are internalized and degraded through interactions with an LRP-2/Megalin. In human, an alternately spliced 50 kDa isoform of Clusterin (nCLU) lacks the signal peptide and remains intracellular. This molecule is neither glycosylated nor cleaved into alpha and beta chains. In the cytoplasm, nCLU destabilizes the actin cytoskeleton and inhibits NF kappa B activation. Cellular exposure to ionizing radiation promotes the translocation of nCLU to the nucleus where it interacts with an Ku70 and promotes apoptosis. This function contrasts with an the cytoprotective effect of secreted Clusterin. During colon cancer tumor progression there is a downregulation of the intracellular form and an upregulation of the glycosylated secreted form.
Hepatocyte growth factor receptor (HGFR), also known as c-Met or mesenchymal-epithelial transition factor (MET), is a receptor tyrosine kinase (RTK) that has been shown to be overexpressed and/or mutated in a variety of malignancies. HGFR protein is produced as a single-chain precursor, and HGF is the only known ligand. Normal HGF/HGFR signaling is essential for embryonic development, tissue repair or wound healing, whereas aberrantly active HGFR has been strongly implicated in tumorigenesis, particularly in the development of invasive and metastatic phenotypes. HGFR protein is a multifaceted regulator of growth, motility, and invasion, and is normally expressed by cells of epithelial origin. Preclinical studies suggest that targeting aberrant HGFR signaling could be an attractive therapy in cancer.
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