Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion.
The cell adhesion molecule L1 has been implicated in a variety of motile processes, including neurite extension, cerebellar cell migration, extravasation, and metastasis. Homophilic or heterophilic L1 binding and concomitant signaling have been shown to promote cell motility in the short term. In this report, L1 is also shown to induce and maintain a motile and invasive phenotype by promoting gene transcription. In the presence of serum or platelet-derived growth factor, L1 promotes heightened and sustained activation of the extracellular signal-regulated kinase pathway. Activation of this pathway then induces the expression of motility- and invasion-associated gene products, including the beta(3)-integrin subunit, small GTPases, and the cysteine proteases cathepsin-L and -B. Induction of integrin alpha(v)beta(3) and rac-1 is shown to contribute directly to L1-dependent haptotaxis, whereas induction of cathepsins-L and -B promotes matrix invasion. This study provides a novel translational mechanism to account for the association between L1 expression and motile processes involved in metastasis and development.
Silletti
Steve
S
Department of Pediatrics, The Whittier Institute, and Moores Comprehensive Cancer Center, University of California at San Diego, La Jolla, California 92037, USA.
Yebra
Mayra
M
Perez
Brandon
B
Cirulli
Vincenzo
V
McMahon
Martin
M
Montgomery
Anthony M P
AM
D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology*; D016895:Culture Media, Serum-Free; D003546:Cysteine Endopeptidases; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D011485:Protein Binding; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D016895:Culture Media, Serum-Free; D006133:Growth Substances; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D039842:Neural Cell Adhesion Molecule L1; D020928:Mitogen-Activated Protein Kinases; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D020830:rac1 GTP-Binding Protein