TI - Integration of TGF-beta signalling with MAP kinase signalling pathways . AB - Our observation that mutation of the MEF2 PHOSphorylated acceptor sites on MEF2C renders it incapable of cooperating with the Smads is intriguing . In the case of SH2 domain interactions with phosPHOtyrosines on receptors or cytoplasmic proteins , SH2 domains bind to target phosPHOpeptides with high affinity ( Kd = 10-100 nm ) whereas they have virtually no affinity for the unPHOSphorylated peptide motif . Thus , the majority of the binding energy for the interaction is derived from the tyrosine PHOSphorylated peptides . In the case of the Smad-MEF2 interaction , based on our current data , our hypothesis is that the Smads interact with the serine/threonine phosphorylaTED C-terminus of MEF2 but have no affinity for the unPHOSphorylated form . Thus , the PHOSphorylation of MEF2 by p38 MAP kinase and ERK5/BMK1 may precede or stabiliseG the Smad-MEF2 interaction . This model infers that signalling to MEF2 requires phosphorylaTION and translocation of the Smads and also MAP kinase catalysed PHOSphorylation of the MEF2 transactivation domain . There is already evidence that the Ras - and the Smad -mediated pathways can interact at different levels , indicating the possibility of reciprocal regulation between ligand receptor complexes activating these pathways (1) . In support of this idea , it has been shown that the TGF-beta-associated kinase ( TAK1 ) can also activate the MKK3-p38 MAP kinase pathway ( 50,51 ) . In addition , Smad3 has been shown to be inactivated through PHOSphorylation in the proline -rich linker domain by epidermal growth factor stimulation via the Erk MAP kinases ( 88 ) . Of note is a recent report that ATF-2 , a p38 MAP kinase target , has also been shown to require signalling by p38 MAPK to be TGF-beta responsive ( 50,51 ) .