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. 2022 Dec 16;13:1064033. doi: 10.3389/fimmu.2022.1064033

Figure 2.

Figure 2

Signal pathway involving metalloproteinases related to immunity in cancer cells. Tumor Necrosis Factor (TNF) signal pathway: The transmembrane TNF-α (tmTNF-α) cleaved by proteolytic enzyme ADAM17 produced soluble TNF-α (sTNF-α), which binds to TNFR1 and then recruits TNFR-associated death domain (TRADD), TNFR-associated factor (TRF)-1 and TRF-2 generating two different results: mediating caspase activation to apoptosis or leading to activation of the NF-κB and AP-1 for tumor cell proliferation. When tmTNF-α binds to TNFR2 as ligands to inhibite NF-κB mediated activation of anti-apoptotic genes, then apoptosis and tumor suppression will be triggered; as a receptor tmTNF-α transect the reverse signal to promote tumor proliferation by constitutively activating NF-κB. The activity of ADAM17 can be stimulate by pseudoprotease enzyme iRhom2. Transforming growth factor β (TGF-β) signal pathway: MMP9 and MMP2 cleave the inactive latent TGF-β propeptide (LAP) and produce different activated TGF-β proteolytic cleavage products. In the canonical pathway, active TGF-β triggers TGFβRII to phosphorylate TGFβRI, which in turn recognizes and phosphorylate SMAD2 and SMAD3 proteins to interact with SMAD4 to form a complex that can enter the nucleus and regulate the transcription of target genes. For example, down-regulating the expression of proto-oncogene Myc to inhibit cell proliferation, inducing the Snail1 and ZEB1 to promote epithelial mesenchymal transition (EMT) in tumors. The co-aggregation of CD44 and MMP9 can promoted the protein activity of MMP9. Notch signaling pathway: ADAM10 and ADAM17 have been indicated in many studies that they can act on cleaving S2, and subsequent cleavage S3 mediated by γ-secretase occurs in the transmembrane region, leading to the release of Notch intracellular domain (NICD), which translocate into the nucleus and combines Mastermind-like (MAML) and DNA-binding protein Recombination Signal-binding Protein for Immunoglobulin kappa J region (RBPJ) to recruits additional coactivators (CoA) triggering the transcription of target genes, such as Myc, P21, HES1 and so on.