Abstract
FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase(mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed thatSHOC2, a RAS activator, is a FBXW7 substrate.Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 andinduce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block the MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in pancreatic cancer, which correlated with poor patient survival. SHOC2 mutations were found in lung cancer tissues with gain-of-function activity. Collectively, the SHOC2-Raptor interaction triggers negative cross-talk between RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways by targeting SHOC2 for ubiquitylation and degradation.
Highlights
FBXW7 Binds to SHOC2 and Shortens Its Protein HalfLife In the process of characterizing Erbin, a negative regulator of RAS/RAF signal, as a substrate of SCFbTrCP E3 ubiquitin ligase (Xie et al, 2015), we unexpectedly found that SHOC2, a positive regulator of RAS/RAF can be accumulated upon the treatment of MLN4924, a small molecule inhibitor of SCF E3 ligase (Soucy et al, 2009), in a dose -dependent manner in keratinocytes and multiple lung cancer lines (Figures S1A and S1B), suggesting SHOC2 is likely a substrate of SCF E3 ligase
We reported here that upon activation of the mitogen-activated protein kinase (MAPK) signal by growth factor EGF or serum, SHOC2 is phosphorylated at the Thr507 residue within the FBXW7 consensus binding motif, which facilitates its binding to FBXW7 for subsequent ubiquitylation and degradation (Figure 2)
Because SHOC2 is an activator of the RAS-extracellular signal-regulated kinase (ERK) signal, whereas FBXW7 is a tumor suppressor that promotes SHOC2 ubiquitylation and degradation, it is not surprising to observe that two proteins counteract with each other in regulation of the growth and survival of lung cancer cells in an ERK-dependent manner, with FBXW7 acting at the upstream (Figure 3)
Summary
FBXW7, a haploinsufficient tumor suppressor, is the substraterecognizing sub-unit of SCF E3 ubiquitin ligase, which promotes ubiquitylation and degradation of several key molecules governing major signaling pathways, including cellular myelocytomatosis (c-MYC) (Welcker et al, 2004; Yada et al, 2004), nuclear factor kB2 (NFkB2) (p100) (Fukushima et al, 2012), myeloid cell leukemia-1 (MCL-1) (Inuzuka et al, 2011; Wertz et al, 2011), neurofibromatosis type 1 (NF1) (Tan et al, 2011), c-JUN (Gu et al, 2007; Wei et al, 2005), Notch (O’Neil et al, 2007), Cyclin E (Koepp et al, 2001), and early meiotic induction protein 1 (EMI1) (Bernis et al, 2007; Margottin-Goguet et al, 2003; Wang et al, 2014). FBXW7 interacts with a specific conserved Cdc phosphodegron sequence ((L)-X-pT/pS-P-(P)-X-pS/pT) on its substrates. Proper phosphorylation of the substrate is required in most cases for FBXW7 to recognize and target its substrate for ubiquitylation (Welcker and Clurman, 2008). Low levels of FBXW7 expression in cancer tissues correlate with a poor prognosis, higher grade of malignancy, and dedifferentiation of cancer cells in several cancers (Berger et al, 2017; Gao et al, 2014; He et al, 2017; Wang et al, 2016; Wang et al, 2012; Welcker and Clurman, 2008). Extracellular signal-regulated kinase (ERK) was reported to phosphorylate FBXW7 and promote its self-ubiquitylation in pancreatic cancer cells (Ji et al, 2015)
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