RSK Is a Principal Effector of the RAS-ERK Pathway for Eliciting a Coordinate Promotile/Invasive Gene Program and Phenotype in Epithelial Cells

Abstract

SUMMARY The RAS-stimulated RAF-MEK-ERK pathway confers epithelial cells with critical motile and invasive capacities during embryonic development, tissue regeneration and carcinoma progression. Yet many mechanisms by which ERK exerts this control remain elusive. Here, we demonstrate that the ERK-activated kinase RSK is necessary to induce motility and invasive capacities in non-transformed epithelial cells and carcinoma cells. RSK is moreover sufficient to induce certain motile responses. Expression profiling analysis revealed that a primary role of RSK is to induce transcription of potent pro-motile/invasive gene program by FRA1-dependent and independent mechanisms. Strikingly, the program enables RSK to coordinately modulate the extracellular environment, the intracellular motility apparatus, and receptors mediating communication between these compartments to stimulate motility and invasion. These findings uncover a general mechanism whereby the RAS-ERK pathway controls epithelial cell motility by identifying RSK as a key effector, from which emanates multiple highly coordinate transcription-dependent mechanisms for stimulation of motility and invasive properties.

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

“…In A549 cells, FRA-1 overexpression induces in vitro invasion and anchorage-independent growth, along with in vivo metastasis (39). More recently, FRA-1 has been implicated in the control of EMT in response to the RAS-MEK-ERK pathway in multiple tumor cell systems (40)(41)(42)(43). Interactions between SMAD3/4 and AP-1 components are well-characterized examples of cooperation between transcription factors (44).…”

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

“…Overexpression of the Fra-1 transcription factor in human cancers is strongly linked to tumour growth, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Young and Colburn, 2006;Adiseshaiah et al, 2007;Doehn et al, 2009;Luo et al, 2010). Understanding the mechanisms regulating Fra-1 accumulation in tumour cells is a key issue, but one that is not fully understood.…”

“…The Fos-related antigen-1 (Fra-1) is a Fos family member that is persistently overexpressed in a variety of cancers and tumour cell lines, where it has been reported to regulate cell proliferation, survival, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Kakumoto et al, 2006;Young and Colburn, 2006;Adiseshaiah et al, 2007;Casalino et al, 2007;Doehn et al, 2009;Luo et al, 2010). A number of Fra-1-regulated genes have been implicated in these processes, including modulators of cell cycle progression (CCND1 and CCNA2; Burch et al, 2004;Casalino et al, 2007;Vikhanskaya et al, 2007), epithelial-mesenchymal transitions (ZEB1 and ZEB2; Shin et al, 2010, extracellular matrix degradation (MMP1 and MMP9;Kustikova et al, 1998) and migration (cd44, VEGF, c-met; Ramos-Nino et al, 2003).…”

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

“…Fos‐related antigen 1 plays an important role in the formation of AP‐1 complexes, which regulate the expression of specific genes such as MMP‐1 8, 10. Protein stability is a major regulatory outcome of FRA1 protein expression, and extracellular signal‐regulated kinase (ERK)1/2 signalling is an important mediator of FRA1 protein stability 7.…”