Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization.
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 Ser(1204) and Ser(1248) 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.
Schaefer
A W
AW
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4975, USA.
Kamiguchi
H
H
Wong
E V
EV
Beach
C M
CM
Landreth
G
G
Lemmon
V
V
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002642:Chick Embryo; D004705:Endocytosis; D004789:Enzyme Activation; D039841:Leukocyte L1 Antigen Complex; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D011994:Recombinant Proteins; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases