Although most ERK5 targets are nuclear substrates, ERK5 is also a crucial regulator of cytosolic targets involved in cytoskeleton remodelling, like Akt, p90RSK, SGK, and the focal adhesion kinase (FAK)
[65][84][85][86]. Interestingly, it has been demonstrated that ERK5-signaling suppression in TNBC and PC-3 cell lines lead to a drastic decrease in FAK phosphorylation, motility, and cell adhesion
[87]. In accordance, recent studies have further underlined the critical linkage between the MEK5/ERK5 axis and the maintenance of the invasive capability of TNBC
[88][89], LC, and melanoma
[90] through FAK activation. Additionally, it has been found that ERK5 mainly localizes in the cytoplasm and membrane of ERα-negative BC cells, promoting actin remodeling, cell mobility, and invasion
[91]. Moreover, suppressing the MEK5/ERK5 pathway completely prevented the TGFβ-induced EMT in murine BC cells, forcing at the same time highly metastatic tumor cells into a differentiated epithelial state
[92]. In addition, ERK5 contributes to BC cell migration as an effector of the Breast tumor kinase
[93] Cdc42
[94] and SRC associated in mitosis of 68 kDa signaling pathways
[95]. Different reports have also highlighted the requirement for the upstream ERK5 activator MEKK2 in the migration, motility, and focal adhesion stability of invasive BC cell lines
[96][97]. It is worth noting that MEK5 overexpression in BC cells can also determine a TNF-α chemotherapy-resistant phenotype characterized by the upregulation of several distinct EMT-associated genes
[98]. Furthermore, STAT3 upregulation has been reported to significantly increase the transcription of MEK5, consequently enhancing BC invasiveness and metastasis formation
[18]. Moreover, ERK5 has been reported to sustain the mesenchymal and migratory phenotype of TNBC cells by modulating FRA-1 expression
[99] and regulating matrix-associated genes, integrins, and pro-angiogenic factors
[100]. Strikingly, as revealed by in vivo studies on an orthotopic mouse model, MAPK7 silencing consistently reduced the number of circulating tumor cells and the insurgence of lung metastases
[101]. Other than BC, ERK5 was also reported to be a crucial mediator of migration and invasion in osteosarcoma cell lines, regulating the expression of Slug and MMP-9
[102][103][104]. Furthermore, it has been documented that ERK5 activation is required for Src-mediated transformation and actin cytoskeleton disruption in NIH3T3 cells
[14]. In addition, a series of in vitro experiments revealed that ERK5 pharmacological inhibition significantly decreased the invasiveness of HER-2-overexpressed meningioma cell lines
[105]. ERK5 and its molecular target AP-1 have also been recently associated with the benzidine-induced EMT mechanism among bladder cancer cells
[106]. Furthermore, ERK5 is implicated in the mechanism of podosomes formation of Src-transformed fibroblasts, inducing the Rho GTPase-activating protein 7 and thereby limiting Rho activation
[107]. Moreover, pcDNA-MAPK7-transfected ovarian cancer cell lines displayed a stark increase in invasiveness and migration due to type II collagen upregulation, which was subsequently reversed through a MAPK7 silencing approach
[108]. Similarly, the pharmacological inhibition of MEK5 using the specific kinase inhibitor BIX02189 resulted in a drastic reduction of cell migration in LC cells due to the suppression of the TGF-β1-induced EMT
[109]. A significant association between tumor stage, presence of lymph-node metastasis and ERK5 expression was also identified by using a whole-transcriptome chip to a set of 35 primary oral squamous cell carcinomas (OSCC)
[90]. In line with these observations, ERK5 expression was found to be increased in almost 60% of patients affected by clear cell renal cell carcinoma (RCC), and associated with the presence of metastasis and more advanced tumor stages
[110]. Interestingly, it has been reported that triggering the EGF/ERK5/MEF2/DNA damage induced apoptosis suppressor (DDIAS) pathway enhanced cancer cells invasion through the expression of β-catenin target genes
[111]. In addition ERK5 has also been identified as a downstream effector of the Protein-tyrosine kinase 6-p130 CRK-associated substrate axis, playing an important role in cancer cells migration and invasion
[112]. Moreover, it has been recently demonstrated that restoring the expression of miR-200b-3p
[60] and miR-429
[113] in glioma cells determined a drastic reduction of cell migration and EMT as a result of ERK5 suppression. In a similar manner, the upregulation of miR-143 in BC induced a marked reduction of ERK5 expression, proliferation, and migration among tumor cells
[114]. Although a great part of the current literature describes ERK5 as a promoter of EMT and cell migration, Chen et al.
[115] identified an opposite function of ERK5 in BC cell line 4T1, which could act as a metastasis suppressor by regulating the mTOR/Akt signaling.