Consequently, the expression profile of the various protein isoforms is often different from normal tissues . Importantly, splice variants can exert different or even opposite functions in comparison to their full-length counterparts. Nevertheless, the specific impact of alternative splicing products, including those of L1CAM, on tumour progression has not been fully elucidated so far. Alternative splicing of the L1CAM mRNA results in a fulllength form and an evolutionary highly conserved splice variant, lacking exons 2 and 27. The FLL1CAM variant consists of six immunoglobulin-like domains, five fibronectin type III repeats, and a short cytoplasmic tail. The SV-L1CAM variant exhibits alterations in the molecular structure N-terminal of the Ig1 region and in the cytoplasmic tail as compared to the full-length L1CAM molecule. In specific, expression of the exon 2 WZ8040 EGFR/HER2 inhibitor peptide sequence comprising only five amino acids affects homophilic and heterophilic binding to neural ligands which are important for growth-promotion of neural cells. The cytoplasmic sequence encoded by exon 27 is a YRSLE motif which is necessary for clathrin-dependent endocytosis and for regulation of L1CAM density at the cell surface. Indeed, internalization of L1CAM was shown to be important for downstream signaling. Moreover, src-mediated phosphorylation of the tyrosine in the YRSLE motif represents a critical regulatory point of L1CAM-mediated adhesion and intracellular signaling. With regard to tumour pathology, overexpression of L1CAM is detected in a variety of cancers and associated with tumour Afatinib growth and metastasis. Consequently, elevated levels of L1CAM often indicate bad prognosis for cancer patients. Furthermore, L1CAM has been proposed as a promising therapeutic target since treatment with anti-L1CAM antibodies has been shown to exhibit significant anti-metastatic effects. Importantly, in none of the previous studies about the contribution of L1CAM to tumour progression, the specific roles of FL-L1CAM and SV-L1CAM have been distinguished. This lack of evidence might be due to the general assumption that FL-L1CAM expression was restricted to neuronal tissues, whereas SV-L1CAM was detected in non-neuronal tissues including tumours and lymphocytes. In the present study, we revised this axiom by demonstrating that FL-L1CAM and SV-L1CAM mRNAs are both expressed in benign ovarian tumours and both increased during progression of human ovarian carcinomas. Furthermore, incubation of different cancer cells with recombinant Hepatocyte growth factor or Transforming growth factor-b1, respectively, both known to promote metastasis, exclusively increased the expression of FL-L1CAM. We further elucidated that overexpression of FL-L1CAM but not of the splice variant SV-L1CAM conferred increased metastatic potential to tumour cells of three different entities.