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 β3-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.
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Abbreviations
- CRABPII:
-
cellular retinoic acid-binding protein II
- Erk:
-
extracellular signal-regulated kinase
- hL1:
-
human L1
- hL1mutS:
-
human L1 with a mutation of S1248A
- hL1mutTS:
-
human L1 with mutations of T1247A and S1248A
- RA:
-
retinoic acid
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Acknowledgements
We thank Verena Gschwend and Natalie Erbe for excellent technical assistance. We thank our colleagues Christian Maerker for technical help with the initial chip analysis and Ilse Novak-Hofer for helpful discussion. This work was supported by grants from Deutsche Krebshilfe to PA and AK (10-1307-3Al and Schwerpunktprogramm: Invasion and Migration) and the EU-FP6 framework programme OVCAD project nr. PE-14034 to PA and MF.
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Gast, D., Riedle, S., Issa, Y. et al. The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies. Oncogene 27, 1281–1289 (2008). https://doi.org/10.1038/sj.onc.1210747
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DOI: https://doi.org/10.1038/sj.onc.1210747
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