The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Herein, we have studied an involvement of RSKs in FGF2/FGFR2-driven behaviours of mammary epithelial and breast cancer cells. We found that both silencing and inhibiting of FGFR2 attenuated phosphorylation of RSKs, whereas FGFR2 overexpression and/or its stimulation with FGF2 enhanced RSKs activity. Moreover, treatment with ERK, Src and p38 inhibitors revealed that p38 kinase acts as an upstream RSK2 regulator. We demonstrate for the first time that in FGF2/FGFR2 signalling, p38 but not MEK/ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359/Ser363, Thr573 and Ser380). In contrast to FGF2-triggered signalling, inhibition of p38 in the EGF pathway affected only RSK2-Tyr529, without any impact on the remaining RSK phosphorylation sites. p38-mediated phosphorylation of RSK2-Tyr529 was crucial for the transactivation of residues located at kinase C-terminal domain and linker-region, specifically, in the FGF2/FGFR2 signalling pathway. Furthermore, we show that FGF2 promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration, which was effectively abolished by treatment with RSKs inhibitor (FMK). These indicate that RSK2 activity is indispensable for FGF2/FGFR2-mediated cellular effects. Our findings identified a new FGF2/FGFR2-p38-RSK2 pathway, which may play a significant role in the pathogenesis and progression of breast cancer and, hence, may present a novel therapeutic target in the treatment of FGFR2-expressing tumours.
Invasion and migration of cancer cells are crucial for the formation of secondary lesions. These require activation of signalling cascades modulated by the number of regulatory molecules. One such molecule is CD151, a member of evolutionary conserved tetraspanin family. CD151 is involved in cell adhesion, motility and cancer progression due to formation of complexes with laminin-binding integrins and regulation of growth factor receptors function (e.g. HGFR, TGFβR, EGFR). Recent studies point to correlation between CD151 expression and high tumour grade in prostate cancer (PCa). Herein, we investigated a possible role of CD151 in communication between PC3 cancer cells and either cancer-associated fibroblasts (CAFs) or osteoblasts, an interplay which is significant for metastasis. The analysis showed that although CAFs strongly enhanced both migration and invasion of PC3 prostate cancer cells, the effect was not dependent on CD151. On the other hand, CD151 was found to promote 3D migration as well as invasive growth in response to osteoblasts-secreted growth factors. Obtained data revealed that knockdown of CD151 abolished activation of pro-migratory/pro-survival kinases (i.e FAK, Src, HSP27) triggered by osteoblasts, along with expression of matrix metalloproteinase-13. This suggests that CD151 participates in communication between PC3 cells and bone microenvironment and the process can be considered as a significant step of PCa progression and metastasis.
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