Model for ErbB signaling in integration of extracellular matrix signals. Transmembrane precursor pro-HB-EGF is cleaved by TACE to HB-EGF, a ligand for erbB1 and erbB4. Binding of HB-EGF to erbB1, and possibly formation of a heterodimer with erbB2, may limit the extent of EMT and also decrease BMP expression. In contrast, activation of erbB2/3 heterodimers by the ECM polysaccharide hyaluronic acid (HA) increases EMT and migration, an effect that appears to be mediated by Ras signaling. Synthesis of HA from glucuronic acid and N-acetylglucosamine (GlcNAc) is dependent on the enzymes UDP-glucose dehydrogenase (UGDH) and hyaluronic acid synthase-2 (HAS-2).