title: Regulated proteolytic processing of LRP6 results in release of its intracellular domain.
abstract: Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of low-density lipoprotein receptor (LDLR) family which cooperates with Frizzled receptors to transduce the canonical Wnt signal. As a critical component of the canonical Wnt pathway, LRP6 is essential for appropriate brain development, however, the mechanism by which LRP6 facilitates Wnt canonical signaling has not been fully elucidated. Interestingly, LRP6 which lacks its extracellular domain can constitutively activate TCF/LEF and potentiate the Wnt signal. Further, the free cytosolic tail of LRP6 interacts directly with glycogen synthase kinase (GSK3) and inhibits GSK3's activity in the Wnt canonical pathway which results in increased TCF/LEF activation. However, whether these truncated forms of LRP6 are physiologically relevant is unclear. Recent studies have shown that other members of the LDLR family undergo gamma-secretase dependent regulated intramembrane proteolysis (RIP). Using independent experimental approaches, we show that LRP6 also undergoes RIP. The extracellular domain of LRP6 is shed and released into the surrounding milieu and the cytoplasmic tail is cleaved by gamma-secretase-like activity to release the intracellular domain. Furthermore, protein kinase C, Wnt 3a and Dickkopf-1 modulate this process. These findings suggest a novel mechanism for LRP6 in Wnt signaling: induction of ectodomain shedding of LRP6, followed by the gamma-secretase involved proteolytic releasing its intracellular domain (ICD) which then binds to GSK3 inhibiting its activity and thus activates the canonical Wnt signaling pathway.
authors.affiliation: Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors.forename: Kaihong
authors.initials: K
authors.lastname: Mi
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004847:Epithelial Cells / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010447:Peptide Hydrolases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D051153:Wnt Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases