TGF-b ve NF-kB sinyal yolaklarının çapraz konuşmasında Malt1 geninin rolü

Transforming growth factor-b (TGF-b) is a cytokine superfamily expressed in a variety of cell types. Through contextual regulation of a large number of genes, TGF-b ligands serve critical functions in key cellular and molecular mechanisms, including cancer cell survival and proliferation. Notably, canonical (Smad-dependent) and non-canonical (Smad-independent) signaling pathways are involved in its activity. Furthermore, TGF-b signaling is known to interact with other intracellular pathways, including MAPK, JNK, JAK/STAT and NF-kB. Importantly, the nuclear factor kappa-B (NF-kB) pathway constitutes a small family of transcription factors found in virtually every cell type and is involved in multiple aspects of biological functions relevant to physiological and pathophysiological processes. The activity of NF-kB pathway is also modulated by both canonical and non-canonical signals. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1), a paracaspase first identified in a subset of MALT lymphoma, is a critical component of NF-kB pathway in several biological contexts. Yet, the role of Malt1 in TGF-b and NF-kB interaction is unknown. Here we report that Malt1 protein potentiates the crosstalk between TGF-b and NF-kB signaling pathways. Mechanistically, through extensive molecular studies in A549 and Huh7 cancer cell lines using RNAi and CRISPR/Cas9 perturbations, we find that Malt1 is a Smad3-dependent target gene of canonical TGF-b signaling. More significantly, TGF-b-mediated Malt1 induction facilitates NF-kB activation. Collectively, our pioneering work provides mechanistic insights into how TGF-b/Smad signaling regulates Malt1 expression and reveals a novel mode of crosstalk between TGF-b and NF-kB signaling pathways.