LRP2 gene

The LRP2 gene (LRP2 stands for: LDL receptor-related protein 2) is a protein-coding gene located on chromosome 2q31.1. An important paralog of this gene is LRP1.

The protein encoded by this gene, Low Density Lipoprotein-Related Protein 2 (LRP2) or megalin, is a multiligand endocytosis receptor expressed in many different tissues, but most notably in absorptive epithelial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding domains bind various macromolecules, including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins and hormones. This protein also plays a role in cell signaling; extracellular ligands include parathyroid hormones and the morphogen Sonic Hedgehog, while cytosolic ligands include MAP kinase scaffolding proteins and JNK-interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculo-acoustic-renal syndrome (FOAR).

The encoded protein is a "multiligand endocytosis receptor". It acts together with CUBN to mediate the endocytosis of high-density lipoproteins. Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B. Mediates tubular uptake and excretion of leptin in the kidney. Also mediates the transport of leptin across the blood-brain barrier by endocytosis at the choroid plexus epithelium. Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of food intake and body weight. Mediates endocytosis and subsequent lysosomal degradation of CST3 in renal proximal tubule cells. Mediates the renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP. Mediates the renal uptake of metallothionein-bound heavy metals. Together with CUBN, mediates the renal reabsorption of myoglobin. Mediates renal uptake and subsequent lysosomal degradation of APOM. Plays a role in selenium homeostasis in the kidney by mediating renal endocytosis of the selenoprotein SEPP1 . Mediates renal uptake of the anti-apoptotic protein BIRC5/Survivin, which may be important for the functional integrity of the kidney (Voll RE et al. 2013).

Mediates renal uptake of the matrix metalloproteinase MMP2 in complex with the metalloproteinase inhibitor TIMP1. Mediates endocytosis of sonic hedgehog protein N product (ShhN), the active product of SHH. Also mediates ShhN transcytosis . Mediates endocytic uptake and degradation of BMP4 in the embryonic neuroepithelium, is required for proper SHH localization in the ventral neural tube and plays a role in pattern formation of the ventral telencephalon. 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 transport of SHH. In the adult brain, it negatively regulates BMP signaling in the subependymal zone, allowing neurogenesis to continue. In astrocytes, it mediates the endocytosis of ALB, which is required for the synthesis of the neurotrophic factor oleic acid. It is involved in neurite branching. During optic nerve development, it is required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells. Mediates endocytotic uptake and clearance of SHH in the retinal margin, protecting retinal progenitor cells from mitogenic stimuli and keeping them in a quiescent state). Plays a role in reproductive organ development by mediating the uptake of androgen and estrogen bound to the sex hormone-binding protein SHBG into reproductive tissues. Mediates endocytosis of angiotensin-2. Also mediates endocytosis of angiotensin 1-7. Binds to the complex of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation. Required for embryonic heart development. Required for normal hearing, possibly through interaction with estrogen in the inner ear.

Diseases associated with LRP2 include Donnai-Barrow syndrome and Alport syndrome.

1. Klassen RB et al. (2004) Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol 287:F393-403.
2. Voll RE et al. (2013) Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule. Am J Physiol Renal Physiol 305:F734-44.