Fig. 9.

Schematic representation of TGFβ-Smads/Erk1/2^MAPK signaling switch in ECs of KD_ITSN TGFβ transmits its signal by binding to type II and type I receptors, resulting in activation of type I receptor and subsequent phosphorylation of R-Smads. ITSN-1s binds mSos [7] and thus, KD_ITSN may increase mSos availability for Grb2 interaction, and preferential formation of ALK5/mSos/Grb2 signaling complex. This may result in ineffective assembly of ALK5/Smad2/SARA complexes and subsequent alteration of the Smad2/3-Erk1/2 signaling balance toward persistent Ras/MEK/Erk1/2 activation. ALK5 functions to activate Ras/Erk1/2^MAPK necessary for restoring pro-survival signaling, lost due to KD_ITSN. This signaling event may suppress Smad2/3 phosphorylation. Note that Smad2/3 phosphorylation can be inhibited not only upon Ras/Erk1/2 activation but also upon Smad1/5/8 activation. Smad1/5/8 phosphorylation downstream of BMPR2 is triggered while the receptor is at the plasma membrane; the transcriptional response is however, dependent on BMPR2 internalization [55]