1. Neurobiology Program, Children's Hospital Boston, Department of Neurology, and
2. CBR Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
4. †Present addresses: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, Massachusetts 02139, USA (H.O.); Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson School of Medicine, Piscataway, New Jersey 08854, USA (R.H.)

Correspondence to: Xi He¹ Correspondence and requests for materials should be addressed to X.H. (Email: xi.he@childrens.harvard.edu).

Abstract

Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease¹. The canonical Wnt/-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6)^{2, 3, 4}, whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction⁵. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a 'dual-kinase' mechanism for LRP6 phosphorylation and activation. Glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling through the promotion of -catenin phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt co-receptor activation, reveal an unexpected and intricate logic of Wnt/-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.

1. Neurobiology Program, Children's Hospital Boston, Department of Neurology, and
2. CBR Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
4. †Present addresses: AVEO Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, Massachusetts 02139, USA (H.O.); Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson School of Medicine, Piscataway, New Jersey 08854, USA (R.H.)

Correspondence to: Xi He¹ Correspondence and requests for materials should be addressed to X.H. (Email: xi.he@childrens.harvard.edu).

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