Abstract
Sur8 (also known as Shoc2) is a Ras-Raf scaffold protein that modulates signaling through extracellular signal-regulated kinase (ERK) pathway. Although Sur8 has been shown to be a scaffold protein of the Ras-ERK pathway, its interaction with other signaling pathways and its involvement in tumor malignancy has not been reported. We identified that Sur8 interacts with the p110α subunit of phosphatidylinositol 3-kinase (PI3K), as well as with Ras and Raf, and these interactions are increased in an epidermal growth factor (EGF)- and oncogenic Ras-dependent manner. Sur8 regulates cell migration and invasion via activation of Rac and matrix metalloproteinases (MMPs). Interestingly, using inhibitors of MEK and PI3K we found Sur8 mediates these cellular behaviors predominantly through PI3K pathway. We further found that human metastatic melanoma tissues had higher Sur8 content followed by activations of Akt, ERK, and Rac. Lentivirus-mediated Sur8-knockdown attenuated metastatic potential of highly invasive B16-F10 melanoma cells indicating the role of Sur8 in melanoma metastasis. This is the first report to identify the role of scaffold protein Sur8 in regulating cell motility, invasion, and metastasis through activation of both ERK and PI3K pathways.
Highlights
Ras proteins are small GTPases that cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound conformations
Because changes in the cell morphology is associated with actin cytoskeletal rearrangement [19], we performed actin staining in shCon-green fluorescent protein (GFP) and shSur8-GFP NIH3T3 cells with or without epidermal growth factor (EGF) treatment (Figure 1B)
The current study is the first to reveal that RasRaf scaffold protein Sur8 plays an essential role in the regulation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathway and is involved in cell migration, invasion, and metastasis
Summary
Ras proteins are small GTPases that cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound conformations. The exchange of GDP to GTP induces a conformational change that allows Ras to interact with various effector molecules, such as Raf and phosphatidylinositol 3-kinase (PI3K), and regulate various cellular responses including proliferation, survival, differentiation, motility, and tumorigenesis [1, 2]. The activated Ras-Raf-ERK cascade is implicated in the activation of various target genes controlling cellular proliferation, differentiation, and transformation [3], as well as cell motility [4, 5]. Activation of the PI3K pathway by oncogenic Ras is implicated in cellular transformation and actin cytoskeleton rearrangement mediated by the www.impactjournals.com/oncotarget small GTPase Rac [7], and binding of Ras to p110α is required for Ras-driven tumorigenesis in mice [8]
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