Meta-Biol

• Pathways

MAPK1 (ERK2) and MAPK3 (ERK1) phosphorylate SMAD2 and SMAD3 on conserved residues in the linker region, which connects the DNA-binding domain and the transcriptional activation domain. ERK-mediated phosphorylation leads to cytosolic retention of SMAD2 and SMAD3 and inhibits TGF-beta signaling (Kretzschmar et al. 1999). Potential ERK phosphorylation residues in SMAD2 are T220, S245, S250 and S255, and in SMAD3 they are T179, S213, S204 and S208 (Kretzschmar et al. 1999). The residue S250 in SMAD2 was shown to be phosphorylated by ERKs in several studies (Rostam et al. 2016, Talati et al. 2018). The corresponding site in SMAD3 is residue S208, and it was shown to be the most prominent ERK phosphorylation site (Matsuura et al. 2005). Only these two sites have been annotated as targets of ERK-mediated phosphorylation. Additional sites will be annotated as more information becomes available.

In addition to inhibitory phosphorylation of SMAD2 and SMAD3 by ERKs, an activating phosphorylation of SMAD2 on S8 by MAPK3 has also been reported (Funaba et al. 2002).