1. ¹Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany
2. ²Institute for Experimental Oncology and Therapy, Technical University of Munich, Munich, Germany
3. ³German Cancer Research Center, Heidelberg, Germany
4. ⁴Department of Pathology, Kaplan Medical Center, Rehovot, Israel

Correspondence: Dr P Altevogt, Tumor Immunology Programme, D010, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg D-69120, Germany. E-mail: P.Altevogt@dkfz.de

Received 22 March 2007; Revised 3 July 2007; Accepted 10 July 2007; Published online 22 October 2007.

Abstract

L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule involved in cell migration and axon guidance in the developing nervous system. L1 is also overexpressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes. Here, we show that a mutation in the cytoplasmic portion of L1 (T1247A, S1248A) abrogates Erk activation, blocks cell migration on extracellular matrix proteins and did not augment tumor growth in non-obese diabetic/severe combined immuno-deficient mice. In cells expressing mutant L1, the induction of Erk-dependent genes such as 3-integrin, cathepsin-B and several transcription factors is eliminated and the invasive phenotype is abrogated. L1 antibodies showed similar effects. They prevented Erk activation and interfered with the Erk-dependent gene expression pattern. These findings provide a rationale for the mode of action of L1 antibodies and suggest that interference with L1 function could become a valuable target for therapy.