The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies.
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 beta3-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.
Gast
D
D
Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany.
Riedle
S
S
Issa
Y
Y
Pfeifer
M
M
Beckhove
P
P
Sanderson
M P
MP
Arlt
M
M
Moldenhauer
G
G
Fogel
M
M
Krüger
A
A
Altevogt
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003593:Cytoplasm / Q000737:chemistry / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D039842:Neural Cell Adhesion Molecule L1 / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary
D000911:Antibodies, Monoclonal; D039842:Neural Cell Adhesion Molecule L1