LRP8/ApoER2 (F6T1L) Rabbit Monoclonal Antibody #81258

Low-density lipoprotein receptor-related protein 8/Apolipoprotein E receptor 2 (LRP8/ApoER2) is a type-I transmembrane protein belonging to the low-density lipoprotein receptor (LDLR) family. LRP8/ApoER2 shares a similar structure with LDLR family members and very low-density lipoprotein receptor (VLDLR). The N-terminal extracellular region of these proteins consists of a ligand-binding domain, three epidermal growth factor (EGF) precursor-like repeats, a YWTD β-propeller domain, and an O-linked sugar domain (OLSD). The extracellular region is followed by a single transmembrane domain and a C-terminal cytoplasmic tail. The C-terminal cytoplasmic tail contains an NPxY motif that is important for trafficking and signal transduction (1). There are many reported alternatively spliced isoforms of LRP8/ApoER2, some of which lack one or more of these structures. These splicing events have varying effects on glycosylation, ligand binding, and both extracellular and intracellular processing events. These splice variants display distinct spatiotemporal expression patterns in humans and mice, and have various implications for receptor function, including downstream trafficking and signaling in health and disease (2-5).

LRP8/ApoER2 and VLDLR are the two canonical receptors of reelin, a secreted glycoprotein critical for neuronal development and health. Upon binding, these receptors cluster, driving the clustering and tyrosine phosphorylation of the intracellular adaptor protein Disabled 1 (Dab1) by the Src family kinases (SFK), Src and Fyn. This leads to downstream signaling cascades that regulate various functions, including neuronal migration, dendritic growth and maturation, synaptogenesis, synaptic plasticity, cell adhesion, and proliferation (6-8). Loss or dysfunction of reelin signaling is associated with neurodevelopmental disorders, including lissencephaly and autism spectrum disorder (ASD), as well as psychiatric disorders, including schizophrenia, bipolar disorder, and depression. Reelin dysfunction is also implicated in the etiology of neurodegenerative disorders, including ataxias, traumatic brain injury (TBI), and Alzheimer’s disease (AD) (6,9). The two pathological hallmarks of AD are extracellular accumulation of amyloid beta (Aβ) plaques, driven by amyloidogenic processing of the Aβ precursor protein (APP), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Studies suggest that reelin and other components of this signaling pathway can act to both reduce amyloidogenic processing of APP and inhibit GSK-3β, a kinase heavily involved in the hyperphosphorylation of tau (8-10). LRP8/ApoER2 also binds several ligands beyond reelin, including ApoE, thrombospondin, f-spondin, clusterin, and selenoprotein P (Sepp1). These interactions promote diverse signaling events that are important for neurodevelopment, synaptic plasticity, learning, and memory. These proteins and signaling cascades also have implications in the development of cancer and neurodegeneration (1).