Fig. 5

The TGF-β pathway, modulated by NEDD8, contributes to tumor progression by increasing ECM protein production, regulating ECM remodeling enzymes, promoting epithelial-to-mesenchymal transition, and activating CAFs. Furthermore, neddylation, facilitated by NEDD8, indirectly regulates the TGF-β pathway by stabilizing its signaling through c-CBL, potentially enhancing tumor invasiveness and malignancy. Simultaneously, the Hippo pathway, through the ubiquitination of MST1 and LATS1/2 by CUL7 and CUL4 respectively, plays a crucial role in tumorigenesis. MST1 inhibits the kinase cascade, including LATS1 and LATS2 activation, leading to the phosphorylation of the transcriptional co-activators YAP and TEAD, key downstream effectors of the Hippo pathway, thereby modulating tumor cell growth. Thus, both the TGF-β and Hippo pathways together form a complex network influencing tumor development. N8, neural precursor cell expressed developmentally downregulated protein 8; TGF-β, transforming growth factor-β; CAFs, cancer-associated fibroblasts; c-CBL, casitas b-lineage lymphoma; UBE2M, ubiquitin-conjugating enzyme E2 M; ECM, extracellular matrix; MST1, mammalian STE20-like protein kinase 1; LATS1 and LATS2, Large tumor suppressor kinase 1 and 2; YAP, Yes-associated protein; TEAD, TEA domain. Created with BioRender.com.