LRP2 : LDL receptor related protein 2
Description
The LRP2 (LDL receptor related protein 2) is a protein-coding gene located on chromosome 2.
The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream. Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis), and is also involved in transporting the ligands of a related receptor called cubulin. Megalin is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules).
LRP2 is a multiligand endocytic receptor that acts together with CUBN to mediate endocytosis of high-density lipoproteins. It mediates the receptor-mediated uptake of polybasic drugs like aprotinin, aminoglycosides, and polymyxin B. In the kidney, LRP2 mediates the tubular uptake and clearance of leptin. It also transports leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium. Endocytosis of leptin in neuronal cells is crucial for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight. LRP2 mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells. It mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP. It also mediates renal uptake of metallothionein-bound heavy metals. Together with CUBN, LRP2 mediates renal reabsorption of myoglobin. It mediates renal uptake and subsequent lysosomal degradation of APOM. LRP2 plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1. It mediates renal uptake of the antiapoptotic protein BIRC5/survivin, which may be important for functional integrity of the kidney. LRP2 mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1. LRP2 mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH, and also mediates ShhN transcytosis. In the embryonic neuroepithelium, LRP2 mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube, and plays a role in patterning of the ventral telencephalon. LRP2 is required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH. During neurulation, LRP2 is required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1, which is necessary for neural tube closure. In the adult brain, LRP2 negatively regulates BMP signaling in the subependymal zone, enabling neurogenesis to proceed. In astrocytes, LRP2 mediates endocytosis of ALB, which is required for the synthesis of the neurotrophic factor oleic acid. LRP2 is involved in neurite branching. During optic nerve development, LRP2 is required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells. LRP2 mediates endocytic uptake and clearance of SHH in the retinal margin, which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent. LRP2 plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG. LRP2 mediates endocytosis of angiotensin-2 and also mediates endocytosis of angiotensis 1-7. LRP2 binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation. LRP2 is required for embryonic heart development and is also required for normal hearing, possibly through interaction with estrogen in the inner ear.
LRP2 is also known as DBS, GP330, LRP-2.
