nonSMAD

Non-SMAD signaling refers to SMAD-independent signaling pathways activated by transforming growth factor-beta (TGF-β) family receptors and, in some contexts, by related serine/threonine kinase receptors. While canonical SMAD signaling transduces nuclear transcriptional responses, non-SMAD pathways provide rapid, often transcription-independent, and complementary cellular responses that shape the overall outcome of TGF-β signaling.

The major non-SMAD pathways include activation of mitogen-activated protein kinases (MAPKs) such as ERK, JNK, and p38 through adaptor proteins like Shc/Grb2/SOS and through the TAK1–TAB1 complex. Other important routes involve phosphoinositide 3-kinase (PI3K) and AKT, and signaling through Rho-like GTPases (RhoA, Rac1, Cdc42) that regulate cytoskeletal dynamics and cell motility. In various cells, NF-κB signaling can be engaged via TRAF6 and TAK1, linking TGF-β to inflammatory gene expression. Crosstalk with JAK/STAT, NFAT, and other pathways has been observed, underscoring the integrated nature of cellular signaling networks.

Receptor involvement centers on TGF-β receptor type I and II kinases, which recruit adaptor proteins and kinases that drive non-SMAD outputs independently of SMAD activation. Non-SMAD signaling often operates in parallel with SMAD pathways, modulating the duration and intensity of responses such as cell migration, survival, differentiation, and extracellular matrix production. Dysregulation of these routes has been associated with fibrosis, cancer progression, and vascular diseases, making non-SMAD signaling a focus of ongoing research and therapeutic interest.