Fig. 5.

ADAMs mediate negative signaling feedback via RTK shedding. (A) Full-length p-HER2 and p-HER4 levels increase with 1.5 h BB94 treatment (bead immunoassay). Subsequent 30 min TGFa-treatment did not alter BB94 effects. (B) The 1.5 h BB94 treatment followed by 30 min treatments with NRG1b and HGF lead to higher total, full-length MET (x-axis) and METpY-1349 (y-axis) (Western blot; see SI Appendix, Fig. S15B for images). (C) BB94 increases p-cJun and p-p38 (bead immunoassay). Cells were stimulated with NRG1b and TNFa for 30 min following 1.5 h BB94 treatment. (D) BB94 increases p-Jnk levels in a MET-dependent manner. Following siRNA knockdown of MET, cells were treated with BB94 for 1.5 h and stimulated with NRG1b for 30 min (bead immunoassay). (E) The 24 h proA10 treatment increases surface MET levels, +/− cotreatment with EGF, detected by immunostaining. (F) ADAM-10 knockdown increases basal p-p38 levels in a MET-dependent manner, using 1.5 h treatment with the MET inhibitor foretinib (bead immunoassay). All error bars denote SE. (*P < 0.05, Student t test.)