Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

Wnt-signal transduction is critical for development and tissue homeostasis in a wide range of animal species and is frequently deregulated in human cancers. Members of the Frat/GBP family of glycogen synthase kinase 3β (Gsk3b)-binding oncoproteins are recognized as potent activators of the Wnt/β-cat...

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Published in:	Oncogene Vol. 29; no. 1; pp. 93 - 104
Main Authors:	van Amerongen, R, Nawijn, M C, Lambooij, J -P, Proost, N, Jonkers, J, Berns, A
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 07.01.2010 Nature Publishing Group
Subjects:	Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Apoptosis beta Catenin - genetics beta Catenin - metabolism Binding sites Biological and medical sciences Blotting, Western Carrier Proteins - genetics Carrier Proteins - metabolism Cell Biology Cell Line Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular biology Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Dishevelled Proteins Drosophila Drosophila Proteins Female Fundamental and applied biological sciences. Psychology Genetics Glycogen Synthase Kinase 3 - genetics Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Hematologic and hematopoietic diseases Human Genetics Humans Internal Medicine Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism JNK Mitogen-Activated Protein Kinases - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma, T-Cell - genetics Lymphoma, T-Cell - metabolism Lymphoma, T-Cell - pathology Male Medical sciences Medicine Medicine & Public Health Mice Mice, Inbred C57BL Mice, Knockout Molecular and cellular biology Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Oncology original-article Phosphoproteins - genetics Phosphoproteins - metabolism Phosphorylation Proteins Signal Transduction Survival Analysis TCF Transcription Factors - genetics TCF Transcription Factors - metabolism Transcription Factor AP-1 - genetics Transcription Factor AP-1 - metabolism Transfection Wnt Proteins - genetics Wnt Proteins - metabolism Wnt-signal transduction Gsk3-binding protein lymphomagenesis Diversin planar cell polarity Frat Malignant hemopathy Carcinogenesis Lymphoma Cell signaling lymphoma-genesis Binding protein Signal transduction Lymphoproliferative syndrome C-Onc gene Cellular polarity Onc gene Cancer
ISSN:	0950-9232, 1476-5594, 1476-5594
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Summary:	Wnt-signal transduction is critical for development and tissue homeostasis in a wide range of animal species and is frequently deregulated in human cancers. Members of the Frat/GBP family of glycogen synthase kinase 3β (Gsk3b)-binding oncoproteins are recognized as potent activators of the Wnt/β-catenin pathway in vertebrates. Here, we reveal a novel, Gsk3b-independent function of Frat converging on the activation of JNK and AP-1. Both these have been used as readouts for the noncanonical Frizzled/PCP pathway, which controls polarized cell movements and the establishment of tissue polarity. We find that Frat synergizes with Diversin, the mammalian homolog of the Drosophila PCP protein diego , in the activation of JNK/AP-1 signaling. Importantly, Frat mutants deficient for binding to Gsk3b retain oncogenic activity in vivo , suggesting that Wnt/β-catenin-independent events contribute to Frat-induced malignant transformation. The observed activities of Frat are reminiscent of the dual function of Dishevelled in the Wnt/β-catenin and Frizzled/PCP pathways and suggest that Frat may also function to bridge canonical and noncanonical Wnt pathways.
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ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/onc.2009.310