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. 2014 May 8;111(21):7723–7728. doi: 10.1073/pnas.1318761111

Fig. 5.

Fig. 5.

Model depicting effect of ADAM17 variant on the canonical TGFβ signaling pathway. TGFβ ligand induces heteroligomerization of TβRII and TβRI, activation of TβRI by TβRII, and phosphorylation of Smad2 by TβRI kinase. P-Smad2 oligomerizes with Smad4 to shuttle to the nucleus and instigate a Smad-mediated transcriptional response. The model proposes differential shedding and consequent inactivation of TβRI by the NIH versus C57 variants of ADAM17. The C57 ADAM17 isoform has relatively weak inhibitory activity against TβRI, consequently elevating nuclear P-Smad2/3 and Smad2/3-mediated transcription in cells harboring this variant.