Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization

Andrew W. Schaefer, Hiroyuki Kamiguchi, Eric V. Wong, Carol M. Beach, Gary Landreth, Vance Lemmon

Research output: Contribution to journalArticlepeer-review

159 Scopus citations


L1-mediated axon growth involves intracellular signaling, but the precise mechanisms involved are not yet clear. We report a role for the mitogen-activated protein kinase (MAPK) cascade in L1 signaling. L1 physically associates with the MAPK cascade components Raf-1, ERK2, and the previously identified p90(rsk) in brain. In vitro, ERK2 can phosphorylate L1 at Ser1204 and Ser1248 of the L1 cytoplasmic domain. These two serines are conserved in the L1 family of cell adhesion molecules, also being found in neurofascin and NrCAM. The ability of ERK2 to phosphorylate L1 suggests that L1 signaling could directly regulate L1 function by phosphorylation of the L1 cytoplasmic domain. In L1-expressing 3T3 cells, L1 cross-linking can activate ERK2. Remarkably, the activated ERK localizes with endocytosed vesicular L1 rather than cell surface L1, indicating that L1 internalization and signaling are coupled. Inhibition of L1 internalization with dominant-negative dynamin prevents activation of ERK. These results show that L1-generated signals activate the MAPK cascade in a manner most likely to be important in regulating L1 intracellular trafficking.

Original languageEnglish (US)
Pages (from-to)37965-37973
Number of pages9
JournalJournal of Biological Chemistry
Issue number53
StatePublished - Dec 31 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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