Abstract
BackgroundThe cell adhesion molecule L1 is crucial for mammalian nervous system development. L1 acts as a mediator of signaling events through its intracellular domain, which comprises a putative binding site for 14-3-3 proteins. These regulators of diverse cellular processes are abundant in the brain and preferentially expressed by neurons. In this study, we investigated whether L1 interacts with 14-3-3 proteins, how this interaction is mediated, and whether 14-3-3 proteins influence the function of L1.Methodology/Principal FindingsBy immunoprecipitation, we demonstrated that 14-3-3 proteins are associated with L1 in mouse brain. The site of 14-3-3 interaction in the L1 intracellular domain (L1ICD), which was identified by site-directed mutagenesis and direct binding assays, is phosphorylated by casein kinase II (CKII), and CKII phosphorylation of the L1ICD enhances binding of the 14-3-3 zeta isoform (14-3-3ζ). Interestingly, in an in vitro phosphorylation assay, 14-3-3ζ promoted CKII-dependent phosphorylation of the L1ICD. Given that L1 phosphorylation by CKII has been implicated in L1-triggered axonal elongation, we investigated the influence of 14-3-3ζ on L1-dependent neurite outgrowth. We found that expression of a mutated form of 14-3-3ζ, which impairs interactions of 14-3-3ζ with its binding partners, stimulated neurite elongation from cultured rat hippocampal neurons, supporting a functional connection between L1 and 14-3-3ζ.Conclusions/SignificanceOur results suggest that 14-3-3ζ, a novel direct binding partner of the L1ICD, promotes L1 phosphorylation by CKII in the central nervous system, and regulates neurite outgrowth, an important biological process triggered by L1.
Highlights
L1 is a cell adhesion molecule of the immunoglobulin superfamily which is essential for normal development of the mammalian nervous system
Conclusions/Significance: Our results suggest that 14-3-3f, a novel direct binding partner of the L1 intracellular domain (L1ICD), promotes L1 phosphorylation by casein kinase II (CKII) in the central nervous system, and regulates neurite outgrowth, an important biological process triggered by L1
In contrast to the non-mutated protein, no second band appeared over time with the S1181A mutant (Fig. 4C), demonstrating that the upper band observed in the experiments with wild-type L1ICD
Summary
L1 is a cell adhesion molecule of the immunoglobulin superfamily which is essential for normal development of the mammalian nervous system. It has been demonstrated that cell recognition via L1 is important both for axon outgrowth and for neuronal migration (reviewed in [4,5]) These processes are likely to require dynamic control of L1-mediated cell adhesion, for instance by internalization of L1, regulating the availability of L1 on the cell surface. The broad spectrum of 14-3-3 functions includes activation of tyrosine and tryptophan hydroxylases [18], regulation of the Raf-1 oncogene [19,20,21], and modulation of apoptosis [22,23] Consistent with their abundance in the brain, several studies point to an important role of 14-3-3 proteins in the nervous system. Our data indicate that 14-3-3 proteins regulate biological functions of L1
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