Shoc2-tranduced ERK1/2 motility signals — Novel insights from functional genomics

Abstract

The extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway plays a central role in defining various cellular fates. Scaffold proteins modulating ERK1/2 activity control growth factor signals transduced by the pathway. Here, we analyzed signals transduced by Shoc2, a critical positive modulator of ERK1/2 activity. We found that loss of Shoc2 results in impaired cell motility and delays cell attachment. As ERKs control cellular fates by stimulating transcriptional response, we hypothesized that the mechanisms underlying changes in cell adhesion could be revealed by assessing the changes in transcription of Shoc2-depleted cells. Using quantitative RNA-seq analysis, we identified 853 differentially expressed transcripts. Characterization of the differentially expressed genes showed that Shoc2 regulates the pathway at several levels, including expression of genes controlling cell motility, adhesion, crosstalk with the transforming growth factor beta (TGFβ) pathway, and expression of transcription factors. To understand the mechanisms underlying delayed attachment of cells depleted of Shoc2, changes in expression of the protein of extracellular matrix (lectin galactoside-binding soluble 3-binding protein; LGALS3BP) were functionally analyzed. We demonstrated that delayed adhesion of the Shoc2-depleted cells is a result of attenuated expression and secretion of LGALS3BP. Together our results suggest that Shoc2 regulates cell motility by modulating ERK1/2 signals to cell adhesion.

SHOC2 is associated with the survival of breast cancer cells and has prognostic value for patients with breast cancer

“…In this previous study, SHOC2 could alter signaling connections and re-route oncogenic Ras signals to Raf-1 in order to mediate reactivation of the ERK1/2 pathway and facilitate drug resistance in cells (14). SHoc2 has also been shown to be a positive regulator that contributes to the malignant properties of different tumor cells by modulating the growth, transformation, migration and invasion of cancer cells (10,15,16). Our preliminary experiments revealed that SHOC2 was highly expressed in McF-7 and Mda-MB-231 breast cancer cells (data not shown).…”

M-RAS Regulate CDH1 Function in Blastomere Compaction during Porcine Embryonic Development

“…In contrast to the canonical Ras proteins, constitutively active M-Ras has a low transforming activity and is rarely mutated in human cancer (Quilliam et al, 1999); however, gain-of-function mutations in M-RAS have been iden-tified in patients with Noonan syndrome (Higgins et al, 2017). Notably, mutations in one of the distinct effectors of M-RAS, the SHOC2 scaffold, have also been detected in Noonan patients (Cordeddu and Di, 2009;Hannig et al, 2014), and, likewise, Shoc2 has been implicated in cell migratory events (Young et al, 2013;Kaduwal et al, 2015;Jeoung et al, 2016).…”

The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways

“…SHOC2 is an evolutionarily conserved protein, composed of an unstructured N-terminal domain and a long stretch of leucine-rich repeats (LRRS) (Jeoung et al, 2013). The N-terminal domain binds to RAS and RAF to activate ERK1 and ERK2 (Dai et al, 2006; Jeoung et al, 2013; Jeoung et al, 2016). In addition, SHOC2 is upregulated in the majority of human cancers (Young et al, 2013).…”