Cytoplasmic Domain Mutations of the L1 Cell Adhesion Molecule Reduce L1–Ankyrin Interactions

Needham, Leila K.; Thelen, Karsten; Maness, Patricia F.

doi:10.1523/jneurosci.21-05-01490.2001

Cited by 66 publications

(82 citation statements)

References 33 publications

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“…shown that the cytoplasmic SFI GQY motif of L1CAM (aa 1224-1229, which is present in all L1CAM family members and is highly conserved from invertebrates to vertebrates) is essential for ankyrin binding (Garver et al, 1997;Needham et al, 2001). By introducing two pathological missense mutations, namely S1224L and Y1229H, reduced recruitment of ankyrin to the plasma membrane in vitro was observed (Needham et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…By introducing two pathological missense mutations, namely S1224L and Y1229H, reduced recruitment of ankyrin to the plasma membrane in vitro was observed (Needham et al, 2001). Knock-in mice expressing the missense mutation Y1229H exhibit mistargeting of mutant ganglion cell axons from the ventral retina to lateral sites in the contralateral superior colliculus (Buhusi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

Patzke¹,

Acuña²,

Giam³

et al. 2016

J Cell Biol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

Patzke¹,

Acuña²,

Giam³

et al. 2016

J Cell Biol

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“…We investigated two L1 mutants, either lacking the intracellular domain except for the membrane proximal KRS sequence (L1trun) or with the mutation tyrosine 1229 to histidine (L1YH) known to abolish ankyrin binding (32). In 293T cells expressing the truncated form of L1 lacking the intracellular domain (L1trun), basal shedding was found to be strongly increased compared with the full-length form of L1 (L1wt).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

Heiz

Grünberg

Schubiger

et al. 2004

Journal of Biological Chemistry

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The L1 cell adhesion molecule and its soluble form are tumor-associated proteins and potential markers for tumor staging as well as targets for therapeutic intervention. Soluble L1 is produced by metalloprotease-mediated ectodomain shedding of L1. We investigated effects of hepatocyte growth factor (HGF), a growth factor shown to increase invasiveness of renal carcinoma cells, on ectodomain shedding of L1 from these cells. All of the tested L1-positive renal carcinoma cell lines released a 180-kDa form of L1 into the medium. In the presence of serum, addition of HGF led to a dose-dependent increase in L1 shedding with a maximum reached at 5 ng/ml. In contrast, L1 shedding was inhibited by glial cell linederived neurotrophic factor (GDNF). The tyrosine kinase inhibitor Genistein reduced basal and HGFstimulated L1 shedding, indicating that protein phosphorylation is involved. To investigate the role of the L1 intracellular domain, two mutants of the L1 cytoplasmic part were constructed. L1trun lacking the complete intracellular domain showed enhanced basal shedding. In a L1YH mutant, containing the mutation tyrosine 1229 to histidine that deletes the ankyrin binding motif of L1, basal shedding was reduced. Disruption of actin assembly by cytochalasin D also reduced shedding of L1. These results indicate that the cytoplasmic domain regulates basal shedding of L1, and association with the cytoskeleton through the L1 ankyrin binding site is involved. HGF stimulated L1 shedding in both mutants, indicating that receptor-mediated phosphorylation in the L1 cytoplasmic domain is not required for HGF-stimulated shedding.The L1 cell adhesion molecule (L1) 1 was originally described as a protein of the nervous system, and mutated forms of L1 are linked to severe neurological pathologies referred to as MASA syndrome (1). A non-neuronal isoform of L1 lacking exons 2 and 27 is expressed at low levels in the normal adult human kidney (2) as well as during renal development (3). In contrast, high expression of L1 was found in 8 of 12 renal tumor cell lines and in some renal tumors (2). 2 It was shown that the cell-bound form of L1 can serve as a target for radioimmunodiagnosis of metastatic neuroblastoma (4), and L1 may also be a marker and therapeutic target for certain renal cancers.In cultured cell lines originating from a number of different tumors the L1 ectodomain was found to be cleaved proximal to the cell membrane by metalloproteases, followed by release of soluble L1 into the medium (5-7). Ectodomain shedding of L1 could be stimulated by phorbol esters and vanadate, indicating that phosphorylation events regulate L1 release (6). In cell culture soluble L1 substrate was found to stimulate cellular motility and migration (8). Release of soluble L1 is not restricted to cells in culture as soluble L1 was recently detected in serum samples of patients with ovarian and uterine tumors and is believed to lead to increased cell migration and metastatic spread in these malignancies (9).Here we investigated whether hepatocyte grow...

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“…L1-CAM-ankyrin interactions are regulated by tyrosine phosphorylation at the conserved ankyrin binding site in the L1-cytoplasmic tail (comprised of the amino acid sequence FIGQY); tyrosine to histidine substitutions at this site inhibit L1-mediated recruitment of ankyrin to the cell membrane (Zhang et al, 1998;Needham et al, 2001;Gil et al, 2003). Similarly, the activation of receptor-tyrosine kinases by their ligands drives indirectly the phosphorylation of the FIGQY tyrosine in vertebrate L1-family members and inhibits L1-CAM-ankyrin interactions, suggesting that phosphorylation plays a central role in the regulation of ankyrin binding to L1-CAM Gil et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

MAP Kinase Pathway–dependent Phosphorylation of the L1-CAM Ankyrin Binding Site Regulates Neuronal Growth

Whittard

Sakurai

Cassella

et al. 2006

MBoC

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The growth of neuronal processes depends critically on the function of adhesion proteins that link extracellular ligands to the cytoskeleton. The neuronal adhesion protein L1-CAM serves as a receptor for nerve growth-promoting proteins, a process that is inhibited by the interaction between L1-CAM and the cytoskeleton adaptor ankyrin. Using a novel reporter based on intramolecular bioluminescence resonance energy transfer, we have determined that the MAP kinase pathway regulates the phosphorylation of the FIGQY motif in the adhesion protein L1-CAM and its interaction with ankyrin B. MAP kinase pathway inhibitors block L1-CAM-mediated neuronal growth. However, this blockade is partially rescued by inhibitors of L1-CAM-ankyrin binding. These results demonstrate that the MAP kinase pathway regulates L1-CAMmediated nerve growth by modulating ankyrin binding, suggesting that nerve growth can be regulated at the level of individual receptors.

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Cytoplasmic Domain Mutations of the L1 Cell Adhesion Molecule Reduce L1–Ankyrin Interactions

Cited by 66 publications

References 33 publications

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

MAP Kinase Pathway–dependent Phosphorylation of the L1-CAM Ankyrin Binding Site Regulates Neuronal Growth

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