A Fragment of Adhesion Molecule L1 Binds to Nuclear Receptors to Regulate Synaptic Plasticity and Motor Coordination

Kraus, Kristina; Kleene, Ralf; Henis, Melad; Braren, Ingke; Kataria, Hardeep; Sharaf, Ahmed; Loers, Gabriele; Schachner, Melitta; Lutz, David

doi:10.1007/s12035-018-0901-7

Cited by 19 publications

(40 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, we have found a remarkable accumulation of L1CAM in the nucleus of Ov90-L1CAM cells. While this may be an artifact deriving from the ectopic expression of the protein, it is consistent with previous observations of nuclear translocation of L1CAM in various cell types including OC cells [11,31,47]. In those studies, nuclear L1CAM appeared to impact a wide range of cellular functions by regulating the expression of specific genes, most likely via interacting with DNA-binding such as transcription factors and/ or with DNA itself [11,39].…”

Section: Discussionsupporting

confidence: 90%

L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

Giordano

Decio

Battistini

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

show abstract

Section: Discussionsupporting

confidence: 90%

L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

Giordano

Decio

Battistini

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Only one major L1 fragment with an apparent molecular weight of 140 kDa was observed in immunoblot analysis using an antibody against extracellular epitopes after immunoprecipitation with an antibody against epitopes in the Ig‐like domains. Since L1‐135 is concomitantly generated together with L1‐70 by a proteolytically active MBP form (Kraus, et al., 2018; Kraus, et al., 2018; Lutz et al., 2012, 2016; Lutz, et al., 2014; Lutz, et al., 2014), we propose that this major extracellular L1 fragment represents L1‐135. Mass spectrometry verified that the predominant 140 kDa fragment represents L1‐135, which derives from MBP‐mediated cleavage at position 687 in the first FNIII domain and comprises amino acids 20–687.…”

Section: Discussionmentioning

confidence: 88%

“…Using mouse brain homogenates, only one major L1 fragment with an apparent molecular weight of 80 kDa was detected in immunoblot analysis by antibodies against intracellular epitopes after immunoprecipitation with antibody C‐2 directed against intracellular epitopes or with the antibodies 555 and 557 directed against epitopes within the second and third FNIII domain. Since these epitopes are present only in L1‐70 and not in L1‐80, we conclude that this major L1 fragment represents L1‐70 which is generated by cleavage at position 687 in the first FNIII domain and thus comprises amino acids 688–1260 (Kraus, et al., 2018; Kraus, et al., 2018; Lutz et al., 2012, 2016; Lutz, et al., 2014; Lutz, et al., 2014). Mass spectrometry supported the notion that the 80 kDa fragment represents L1‐70.…”

Section: Discussionmentioning

confidence: 90%

“…L1 consists of a C‐terminal intracellular tail, a transmembrane domain, and an extracellular N‐terminal part comprising six immunoglobulin‐like (Ig) domains and five fibronectin type III (FNIII) homologous domains (Appel et al., 1993; Holm et al., 1995). Full‐length L1 can undergo proteolytic processing to release soluble and transmembrane fragments, which are important for the beneficial functions of L1 in the nervous system (Kalus et al., 2003; Kraus, et al., 2018; Kraus, et al., 2018; Lutz et al., 2012, 2014, 2016, 2017; Lutz, et al., 2014; Mechtersheimer et al., 2001; Silletti et al., 2000).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Revisiting the proteolytic processing of cell adhesion molecule L1

Kleene

Lutz

Loers

et al. 2020

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

The important functions of cell adhesion molecule L1 in the nervous system depend on diverse proteolytic enzymes which generate different L1 fragments. It has been reported that cleavage in the third fibronectin type III (FNIII) homologous domain generates the fragments L1-80 and L1-140, while cleavage in the first FNIII domain yields the fragments L1-70 and L1-135. These results raised questions concerning the L1 cleavage sites. We thus generated gene-edited mice expressing L1 with mutations of the cleavage sites either in the first or third FNIII domain. By immunoprecipitations and immunoblot analyses using brain homogenates and different L1 antibodies, we show that L1-70 and L1-135 are generated in wild-type mice, but not or only to a low extent in L1 mutant mice. L1-80 and L1-140 were not detected in wild-type or mutant mice. Mass spectrometry confirmed the results from immunoprecipitations and immunoblot analyses. Based on these observations, we propose that L1-70 and L1-135 are the predominant fragments in the mouse nervous system and that the third FNIII domain is decisive for generating these fragments. Treatment of cultured cerebellar neurons with trypsin or plasmin, which were both proposed to generate L1-80 and L1-140 by cleaving in the third FNIII domain, showed by immunoprecipitations and immunoblot analyses that both proteases lead to the generation of L1-70 and L1-135, but not L1-80 and L1-140. We discuss previous observations on the basis of our new results and propose a novel view on the molecular features that render previous and present observations compatible. K E Y W O R D S L1CAM, myelin basic protein, PC5a, plasmin, proteolytic fragments, trypsin | 1103 KLEENE Et aL. | INTRODUC TI ONCell adhesion molecule L1CAM (hereafter abbreviated L1) is involved in multiple and diverse functions that regulate proliferation, survival, and migration of neural cells, neuritogenesis, axonal outgrowth, fasciculation, and guidance as well as myelination and synaptogenesis during nervous system development (for reviews, see Hortsch

show abstract

“…L1YH mice also lose the L1-AnkG-β4-spectrin interaction at the AIS (Tai et al, 2019), and L1 null mice exhibit reduced numbers of hippocampal perisomatic inhibitory synapses (Saghatelyan et al, 2004). L1 mutant mice that harbor mutations in nuclear receptor binding motifs show decreased inhibitory GAD67+ and excitatory vGlut+ synaptic puncta on cerebellar Purkinje cells (Kraus et al, 2018). Ankyrin links other membrane and scaffold proteins to the cytoskeleton to further achieve synaptic stability.…”

Section: Role Of Ankyrin Interaction With Neural Adhesion Molecules In Synaptic Stabilizationmentioning

confidence: 99%

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Duncan

Murphy

Maness

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Mammalian brain circuits are wired by dynamic formation and remodeling during development to produce a balance of excitatory and inhibitory synapses. Synaptic regulation is mediated by a complex network of proteins including immunoglobulin (Ig)- class cell adhesion molecules (CAMs), structural and signal-transducing components at the pre- and post-synaptic membranes, and the extracellular protein matrix. This review explores the current understanding of developmental synapse regulation mediated by L1 and NCAM family CAMs. Excitatory and inhibitory synapses undergo formation and remodeling through neuronal CAMs and receptor-ligand interactions. These responses result in pruning inactive dendritic spines and perisomatic contacts, or synaptic strengthening during critical periods of plasticity. Ankyrins engage neural adhesion molecules of the L1 family (L1-CAMs) to promote synaptic stability. Chondroitin sulfates, hyaluronic acid, tenascin-R, and linker proteins comprising the perineuronal net interact with L1-CAMs and NCAM, stabilizing synaptic contacts and limiting plasticity as critical periods close. Understanding neuronal adhesion signaling and synaptic targeting provides insight into normal development as well as synaptic connectivity disorders including autism, schizophrenia, and intellectual disability.

show abstract

A Fragment of Adhesion Molecule L1 Binds to Nuclear Receptors to Regulate Synaptic Plasticity and Motor Coordination

Cited by 19 publications

References 92 publications

L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

Revisiting the proteolytic processing of cell adhesion molecule L1

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Contact Info

Product

Resources

About