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Ras regulates SCF-beta-TrCP activity and specificity via its effector NORE1A

Significance Statement

 

The WNT/β-catenin signaling pathway plays an important role in both development and tumorigenesis.  Stimulation of cells by Wnt ligand activates β-catenin, a nuclear transcriptional co-regulator and a key component of adherence junctions. β-catenin is regulated by phosphorylation by a complex of APC/Axin/GSK3β and subsequent recognition and degradation by the β-TrCP ubiquitin ligase complex.  Mutants of β-catenin that cannot be degraded are common in human cancer and act as constitutively activated oncogenes.  Thus control of β-catenin protein levels is essential for normal cellular homeostasis. Ras is the most frequently activated oncogene found in human cancer.   The relationship of the Ras and the WNT/β-catenin pathways is complex.  Ras can either activate or inhibit the pathway under different cellular conditions.  The mechanisms responsible for the interaction of the two pathways are poorly understood. We now show that the Ras effector NORE1A (RASSF5) serves as the key link between the Ras and WNT/β-catenin pathways. We show that NORE1A forms a direct, Ras-regulated endogenous complex with β-TrCP and scaffolds it to β-catenin, thus promoting β-catenin ubiquitination and degradation.  We show that NORE1A and  β-TrCP synergize to induce cell death, and that it is the levels of NORE1A in a cell that dictate if Ras has a net positive or negative effect on β-catenin protein levels. NORE1A is a tumor suppressor that is frequently down-regulated in human cancers.   This work reveals a completely new mechanism for NORE1A function in regulating the WNT/β-catenin pathway.  Moreover, β-TrCP has multiple other targets that play highly important roles in cellular growth, differentiation and transformation such as: YAP, TAZ, NOTCH, GLI, SNAIL and TWIST.  Therefore, the discovery of a Ras/NORE1A/β-TrCP signaling module has broad ramifications for the role of activated Ras in regulating specific protein stability in cancer.

Figure Legend:   COS-7 cells were transfected with expression constructs GFP β-TrCP and RFP NORE1A.  Fluorescence microscopy shows that NORE1A co-localizes strongly with β-TrCP in speckled bodies in the cell nucleus.

Ras regulates SCF-beta-TrCP activity and specificity via its effector NORE1A. Global Medical Discovery

 

 

 

 

 

 

 

Journal Reference

Schmidt ML1, Donninger H2, Clark GJ3. J Biol Chem. 2014 Nov 7;289(45):31102-10.

1From the Molecular Targets Group, James Graham Brown Cancer Center, Departments of Biochemistry and Molecular Biology.

2Medicine, and 3Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202 [email protected]

Abstract

Ras is the most frequently activated oncogene found in human cancer, but its mechanisms of action remain only partially understood. Ras activates multiple signaling pathways to promote transformation. However, Ras can also exhibit a potent ability to induce growth arrest and death. NORE1A(RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and cell cycle arrest. Expression of NORE1A is frequently lost in human tumors, and its mechanism of action remains unclear. Here we show that  NORE1A  forms a direct, Ras-regulated complex with β-TrCP, the substrate recognition component of the SCF(β-TrCP) ubiquitin ligase complex. This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF(β-TrCP) toward its target β-catenin, resulting in degradation of β-catenin by the 26 S proteasome. However, the action ofRas/NORE1A/β-TrCP is substrate-specific because IκB, another substrate of SCF(β-TrCP), is not sensitive to NORE1A-promoted degradation. We identify a completely new signaling mechanism for Ras that allows for the specific regulation of SCF(β-TrCP) targets. We show that the NORE1Alevels in a cell may dictate the effects of Ras on the Wnt/β-catenin pathway. Moreover, because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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