Fig. 6.

Potential pro-apoptotic mechanisms of miR-217-5p regulating the ERK-MAPK pathway at different sites. MiR-217-5p was shown to directly downregulate PRKCI, ITGAV, BAG3 and MAPK1, connected in a signaling network modulating the ERK-MAPK pathway. Binding of extracellular matrix components to integrins comprising a β (ITGB) and α subunit such as αv (ITGAV) may activate the ERK- MAPK signaling pathway via focal adhesion kinase (FAK) activation, growth factor receptor-bound protein 2 (GRB2), and guanine nucleotide exchange factor son of sevenless (SOS), leading to the activation of the kinase cascade including KRAS, BRAF, MEK, and MAPK1 and the activation of, Phosphoinositide 3-kinase (PI3K)/Akt. These pathways culminate in the activation of survival and proliferation promoting transcription factors including c- myc, c-fos or Ets like protein 1 (Elk1), in the induction and stabilization of anti-apoptotic members (Bcl-2, Bcl-xL, Mcl-1) of the Bcl-2 protein family and the inhibition of pro-apoptotic members including the BH3-only members Bad and Bim promoting the initiation of intrinsic apoptosis via Bax and Bak. PRKCI, ITGAV, BAG3 and MAPK1 promote cell survival and proliferation by induction of transcription factors including NK-κB, AP1 or SOX2, or by induction of the ERK-MAPK pathway via Rac1