[selected findings of recent studies with relevance to Tgf-β superfamily signaling in endocardial EMT have been summarized]. Bmp2 (and possibly also other Bmps) secreted from the AVC myocardium binds to the Bmp and activin type II receptors, which in turn activate type I receptors Alk3 and Alk2 (; ; ; ; ; ; ). Similarly, other Tgf-β superfamily ligands secreted from the myocardium bind to type II receptors, which consecutively leads to activation of Alk5 that is required for endocardial EMT both in the chick () and in the mouse (present study). While a recent study showed that Tgf-β type II receptor (TgfβRII) does not play any non-redundant roles in endocardial transformation in vivo (), the Tgf-β type III receptor was recently shown to play an important role in enhancing binding of Bmp2 to its receptors (). Whether this signaling (red hatched arrow) is dependent on Alk5 activity remains to be seen. Alk2- and Alk3 signaling mediated via Bmp Smads, particularly Smad1, leads to the increased expression of several target genes. Some of these events are likely pathway specific (). Moreover, it has been suggested that activation of Tgf-β Smads in endocardial cells is dependent on Alk2 (blue hatched arrow), but not on Alk3 activity(; ). In a parallel canonical Tgf-β pathway, activated Alk5 signaling via Tgf-β Smads leads to activation of several known target genes (). Simultaneously, phosphorylation of Par6c with the type II receptor-Alk5 complex leads to a rapid degradation of RhoA, which is necessary for dissolution of tight junctions during EMT (; ).
