Expression of L1 cell adhesion molecule (L1CAM) is associated with poor prognosis in a variety of human carcinomas including breast, ovarian and pancreatic ductal adenocarcinoma (PDAC). Recently we reported that L1CAM induces sustained nuclear factor kappa B (NF-kappaB) activation by augmenting the autocrine production of interleukin 1 beta (IL-1beta), a process dependent on interaction of L1CAM with integrins. In the present study, we demonstrate that transforming growth factor beta1 (TGF-beta1) treatment of breast carcinoma (MDA-MB231) and PDAC (BxPc3) cell lines induces an EMT (epithelial to mesenchymal transition)-like phenotype and leads to the expression of L1CAM. In MDA-MB231 cells, up-regulation of L1CAM augmented expression of IL-1beta and NF-kappaB activation, which was reversed by depletion of L1CAM, L1CAM-binding membrane cytoskeleton linker protein ezrin, beta1-integrin or focal adhesion kinase (FAK). Over-expression of L1CAM not only induced NF-kappaB activation but also mediated the phosphorylation of FAK and Src. Phosphorylation was not induced in cells expressing a mutant form of L1CAM (L1-RGE) devoid of the integrin-binding site. FAK- and Src-phosphorylation were inhibited by knock-down of various components of the integrin signalling pathway such as beta1- and alpha5-integrins, integrin-linked kinase (ILK), FAK and the phosphoinositide 3-kinase (PI3K) subunit p110beta. In summary, these results reveal that during EMT, L1CAM promotes IL-1beta expression through a process dependent on integrin signalling and supports a motile and invasive tumour cell phenotype. We also identify important novel downstream effector molecules of the L1CAM-integrin signalling crosstalk that help to understand the molecular mechanisms underlying L1CAM-promoted tumour progression.