| Pathway Name | USP21's Role in Pathway (activator/inhibitor) | Key Substrates in Pathway | Molecular Mechanism | Biological Outcome |
|---|---|---|---|---|
| NF-κB / TNFR1 inflammatory signaling | Inhibitor | RIPK1 | USP21 deubiquitinates RIPK1, suppressing its signaling activity downstream of TNFR1 and thereby reducing NF-κB activation and inflammatory cytokine production (pqac-00000009) | Negative regulation of inflammation and TNFα-driven signaling; likely context-dependent restraint of innate immune activation (pqac-00000009) |
| RIG-I / type I interferon antiviral pathway | Inhibitor | RIG-I | USP21 binds RIG-I and removes activating K63-linked polyubiquitin from RIG-I/RIG-I-CARD, reducing IRF3 phosphorylation and IFN signaling (pqac-00000001, pqac-00000008, pqac-00000011) | Decreased IFN-α/β production and dampened antiviral innate immune responses to RNA viruses (pqac-00000001, pqac-00000011) |
| ERK / MAPK signaling | Activator | MEK2 | USP21 directly deubiquitinates MEK2 by removing K48-linked polyubiquitin, stabilizing MEK2 and enhancing ERK pathway output (pqac-00000002, pqac-00000012) | Increased cell proliferation, cell-cycle progression, and tumor growth, especially in hepatocellular carcinoma models (pqac-00000002, pqac-00000012) |
| Hippo signaling | Generally inhibitor of Hippo growth-suppressive output / activator of proliferative signaling | MARK; USP21 also functionally cooperates with YOD1 | Recent work places USP21 in Hippo regulation through deubiquitination of MARK and interaction with YOD1; this modulates YAP/p-YAP signaling and cell proliferation (pqac-00000007) | Enhanced proliferation and migration in cultured cancer cells through altered Hippo pathway signaling (pqac-00000007) |
| mTORC1 signaling | Activator | MARK3-associated nutrient-scavenging axis; downstream mTORC1 effectors | In KRAS-independent pancreatic cancer growth, cytoplasmic USP21 promotes MARK3-dependent macropinocytosis, sustaining intracellular amino acid supply and enabling mTORC1 activation (pqac-00000006) | Supports nutrient scavenging, anabolic growth, and bypass of KRAS dependency in pancreatic ductal adenocarcinoma (pqac-00000006) |
| Wnt / TCF transcriptional pathway | Activator | TCF7 | USP21 stabilizes TCF7 in the nucleus by deubiquitination, supporting a transcriptional program linked to cancer stemness (pqac-00000006) | Promotes pancreatic cancer stemness and contributes to tumor recurrence/resistance programs (pqac-00000006) |
| Stem cell pluripotency pathway | Activator | Nanog | USP21 interacts with Nanog and specifically removes K48-linked polyubiquitin, stabilizing Nanog; USP21 depletion reduces Nanog and drives differentiation (pqac-00000000, pqac-00000010) | Maintenance of embryonic stem cell self-renewal and pluripotency; loss of USP21 promotes ESC differentiation (pqac-00000000, pqac-00000010) |


*Table: This table summarizes the main signaling pathways currently linked to USP21, indicating whether USP21 acts as a positive or negative regulator, the relevant substrates, and the biological consequences. It is useful for quickly connecting USP21's deubiquitinase activity to specific cellular pathways and phenotypes.*