Dr. Sergio P. Acebrón
Berger BS(1), Acebron SP(2), Herbst J(1), Koch S(1), Niehrs C(2)(3). (2017). Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6. EMBO Rep. 18(5):712-725.
Wnt/β-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky β-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/β-catenin signaling and protects LRP6 from ER-associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling.
Acebron SP(1), Niehrs C(2). (2016). β-Catenin-Independent Roles of Wnt/LRP6 Signaling. Trends Cell Biol. 26(12):956-967.
Wnt/LRP6 signaling is best known for the β-catenin-dependent regulation of target genes. However, pathway branches have recently emerged, including Wnt/STOP signaling, which act independently of β-catenin and transcription. We review here the molecular mechanisms underlying β-catenin-independent Wnt/LRP6 signaling cascades and their implications for cell biology, development, and physiology.
Koch S(1), Acebron SP(1), Herbst J(1), Hatiboglu G(2), Niehrs C(3). (2015). Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation. Cell. 163(5):1225-36.
AbstractCopyright © 2015 Elsevier Inc. All rights reserved.
Comment in Dev Cell. 2015 Nov 23;35(4):401-2.
Huang YL(1), Anvarian Z(1), Döderlein G(1), Acebron SP(2), Niehrs C(3). (2015). Maternal Wnt/STOP signaling promotes cell division during early Xenopus embryogenesis. Proc Natl Acad Sci U S A. 112(18):5732-7.
During Xenopus development, Wnt signaling is thought to function first after midblastula transition to regulate axial patterning via β-catenin-mediated transcription. Here, we report that Wnt/glycogen synthase kinase 3 (GSK3) signaling functions posttranscriptionally already in mature oocytes via Wnt/stabilization of proteins (STOP) signaling. Wnt signaling is induced in oocytes after their entry into meiotic metaphase II and declines again upon exit into interphase. Wnt signaling inhibits Gsk3 and thereby protects proteins from polyubiquitination and degradation in mature oocytes. In a protein array screen, we identify a cluster of mitotic effector proteins that are polyubiquitinated in a Gsk3-dependent manner in Xenopus. Consequently inhibition of maternal Wnt/STOP signaling, but not β-catenin signaling, leads to early cleavage arrest after fertilization. The results support a novel role for Wnt signaling in cell cycle progression independent of β-catenin.
Acebron SP(1), Karaulanov E(2), Berger BS(3), Huang YL(3), Niehrs C(4). (2014). Mitotic wnt signaling promotes protein stabilization and regulates cell size. Mol Cell. 54(4):663-74.
Canonical Wnt signaling is thought to regulate cell behavior mainly by inducing β-catenin-dependent transcription of target genes. In proliferating cells Wnt signaling peaks in the G2/M phase of the cell cycle, but the significance of this "mitotic Wnt signaling" is unclear. Here we introduce Wnt-dependent stabilization of proteins (Wnt/STOP), which is independent of β-catenin and peaks during mitosis. We show that Wnt/STOP plays a critical role in protecting proteins, including c-MYC, from GSK3-dependent polyubiquitination and degradation. Wnt/STOP signaling increases cellular protein levels and cell size. Wnt/STOP, rather than β-catenin signaling, is the dominant mode of Wnt signaling in several cancer cell lines, where it is required for cell growth. We propose that Wnt/STOP signaling slows down protein degradation as cells prepare to divide.
Niehrs C(1), Acebron SP. (2012). Mitotic and mitogenic Wnt signalling. EMBO J. 31(12):2705-13.
Canonical Wnt signalling plays an important role in development, tissue homeostasis, and cancer. At the cellular level, canonical Wnt signalling acts by regulating cell fate, cell growth, and cell proliferation. With regard to proliferation, there is increasing evidence for a complex interaction between canonical Wnt signalling and the cell cycle. Mitogenic Wnt signalling regulates cell proliferation by promoting G1 phase. In mitosis, components of the Wnt signalling cascade function directly in spindle formation. Moreover, Wnt signalling is strongly activated in mitosis, suggesting that 'mitotic Wnt signalling' plays an important role to orchestrate a cell division program. Here, we review the complex interplay between Wnt signalling and the cell cycle.
Niehrs C(1), Acebron SP. (2010). Wnt signaling: multivesicular bodies hold GSK3 captive. Cell. 143(7):1044-6.
AbstractCopyright © 2010 Elsevier Inc. All rights reserved.
Comment on Cell. 2010 Dec 23;143(7):1136-48.
Cruciat CM(1), Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C. (2010). Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 327(5964):459-63.
Wnt/beta-catenin signaling is important in stem cell biology, embryonic development, and disease, including cancer. However, the mechanism of Wnt signal transmission, notably how the receptors are activated, remains incompletely understood. We found that the prorenin receptor (PRR) is a component of the Wnt receptor complex. PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. Moreover, PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system development. The results reveal an unsuspected role for the prorenin receptor, V-ATPase activity, and acidification during Wnt/beta-catenin signaling.