NCAM is ubiquitylated, endocytosed and recycled in neurons

Diestel, Simone; Schaefer, Daniel J.; Cremer, Harold; Schmitz, Brigitte

doi:10.1242/jcs.019729

Cited by 57 publications

(68 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To exit the recycling pathway and enter a route leading to degradation in lysosomes, internalizing receptors must recruit ubiquitin ligases, such as c-Cbl, and must undergo ubiquitinylation (21,34). Unlike their natural ligands, antireceptor antibodies, such as anti-EGFR (15), anti-NCAM (35), and anti-ErbB-2 antibodies (22), induce relatively weak receptor ubiquitinylation. Consistent with immu- Fig.…”

Section: Discussionmentioning

confidence: 99%

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

Ben-Kasus

Schechter²,

Lavi³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

154

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) to ErbB-2/HER2 or to its sibling, the epidermal growth factor receptor (EGFR), prolong survival of cancer patients, especially when combined with cytotoxic therapies. However, low effectiveness of therapeutic mAbs and the evolution of patient resistance call for improvements. Here we test in animals pairs of anti-ErbB-2 mAbs and report that pairs comprising an antibody reactive with the dimerization site of ErbB-2 and an antibody recognizing another distinct epitope better inhibit ErbB-2-overexpressing tumors than other pairs or the respective individual mAbs. Because the superiority of antibody combinations extends to tumor cell cultures, we assume that nonimmunological mechanisms contribute to mAb synergy. One potential mechanism, namely the ability of mAb combinations to instigate ErbB-2 endocytosis, is demonstrated. Translation of these lessons to clinical applications may enhance patient response and delay acquisition of resistance.cancer ͉ growth factor ͉ immunotherapy ͉ signal transduction ͉ tyrosine kinase E rbB-2/HER2 is a member of the epidermal growth factor receptor (EGFR) family. When transactivated, ErbB-2/ HER2 stimulates several downstream signaling cascades, including the mitogen-activated protein kinase cascade (1). This ligand-less receptor is moderately expressed in normal adult tissues, where it regulates cell growth and differentiation. By contrast, amplification of the corresponding gene and consequent overexpression of the HER2/ErbB-2 protein have been reported in 20-30% of tumors of the breast (2-4) and ovary (4). In general, erbB-2 gene amplification associates with enhanced metastatic potential and poor prognosis. Because ErbB-2 is expressed at relatively low levels in normal tissues, it makes an attractive target for immunotherapy. This was originally demonstrated in animals by Greene et al. (5), who targeted Neu, the rodent form of ErbB-2, and later developed this into a widely used clinical strategy (6). The molecular mechanisms underlying the growth-inhibitory effects of anti-ErbB-2 monoclonal antibodies (mAbs) may involve indirect tumor cell cytotoxicity through immunological mechanisms, including antibodydependent cellular cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), increased cancer cell apoptosis, as well as direct interference with signaling cascades (6).Clinical studies established that Trastuzumab (Herceptin), a humanized mAb directed against ErbB-2, is active against ErbB-2-overexpressing metastatic breast cancer, leading to its approval for clinical use (7). The objective response rates to Trastuzumab monotherapy is relatively low (Ϸ15%) and short lived (median duration, 9 months) (8). On the other hand, mAbs seem to display a synergistic effect when combined with chemotherapy, probably because of interruption of ErbB-2-driven survival pathway (9). Yet another strategy, relevant to pancreatic cancer, combines antibodies to EGFR and to ErbB-2 (10). The present study explores an alternative strategy to enhance the therapeutic acti...

show abstract

Section: Discussionmentioning

confidence: 99%

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

Ben-Kasus

Schechter²,

Lavi³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

154

View full text Add to dashboard Cite

show abstract

“…NCAM function can be downregulated by other mechanisms such as ectodomain shedding by ADAM (a disintegrin and metalloprotease) proteases (see [34]) and endocytosis by NCAM ubiquitylation [35]. L1-CAMs are also subject to ADAM-mediated ectodomain shedding and endocytosis by a clathrin-dependent mechanism (Fig.…”

Section: Ncam Signaling and Post-translational Modificationmentioning

confidence: 99%

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

Schmid

Maness

2008

Current Opinion in Neurobiology

203

169

View full text Add to dashboard Cite

Summary of Recent AdvancesNeural cell adhesion molecules (CAMs) of the immunoglobulin superfamily engage in multiple neuronal interactions that influence cell migration, axonal and dendritic projection, and synaptic targeting. Their downstream signal transduction events specify whether a cell moves or projects axons and dendrites to targets in the brain. Many of the diverse functions of CAMs are brought about through homophilic and heterophilic interactions with other cell surface receptors. An emerging concept is that CAMs act as co-receptors to assist in intracellular signal transduction, and to provide cytoskeletal linkage necessary for cell and growth cone motility. Here we will focus on new discoveries that have revealed novel co-receptor functions for the best understood CAMs -L1, CHL1, and NCAM-important for neuronal migration and axon guidance. We will also discuss how dysregulation of CAMs may also bear on neuropsychiatric disease and cancer.

show abstract

“…However, antibodyfeeding internalization assays show that NCAM exerts its function on D 2 R internalization both without and with dopamine stimulation. An explanation for this discrepancy of the results obtained from the two different approaches may be that the application of antibody to live cells in the antibody-feeding assay leads to the clustering of receptors (Diestel et al, 2007), which are likely triggering NCAM and D 2 R internalization even in the absence of dopamine and thus mimic agonist stimulation. Thus, we assume that NCAM mainly functions in agonist-induced D 2 R internalization.…”

mentioning

confidence: 94%

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D₂Receptor Internalization

Xiao¹,

Xu²,

Tereshchenko³

et al. 2009

J. Neurosci.

View full text Add to dashboard Cite

NCAM is ubiquitylated, endocytosed and recycled in neurons

Abstract: Summary NCAM is ubiquitylated, endocytosed and recycled in neurons

Cited by 57 publications

References 62 publications

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D₂Receptor Internalization

Contact Info

Product

Resources

About

NCAM is ubiquitylated, endocytosed and recycled in neurons

Abstract: Summary NCAM is ubiquitylated, endocytosed and recycled in neurons

Cited by 57 publications

References 62 publications

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: Relevance of receptor endocytosis

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D2Receptor Internalization

Contact Info

Product

Resources

About

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D₂Receptor Internalization