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ICAM-5 affects spine maturation by regulation of NMDA receptor binding to ?-actinin.

ABSTRACT: ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP)-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and synaptic distribution of ?-actinin. We found that GluN1 and ICAM-5 partially compete for the binding to ?-actinin; deletion of the cytoplasmic tail of ICAM-5 or ablation of the gene resulted in increased association of GluN1 with ?-actinin, whereas internalization of ICAM-5 peptide perturbed the GluN1/?-actinin interaction. NMDA treatment decreased ?-actinin binding to ICAM-5, and increased the binding to GluN1. Proper synaptic distribution of ?-actinin requires the ICAM-5 cytoplasmic domain, without which ?-actinin tended to accumulate in filopodia, leading to F-actin reorganization. The results indicate that ICAM-5 retards spine maturation by preventing reorganization of the actin cytoskeleton, but NMDA receptor activation is sufficient to relieve the brake and promote the maturation of spines.

SUBMITTER: Ning L

PROVIDER: S-EPMC4365481 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin.

Ning Lin L Paetau Sonja S Nyman-Huttunen Henrietta H Tian Li L Gahmberg Carl G CG

Biology open 20150108 2

ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP)-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and syn ...[more]

PMID: 25572420

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Project description:Progressive metastatic disease is a major cause of mortality for patients diagnosed with multiple types of solid tumors. One of the long-term goals of our laboratory is to identify molecular interactions that regulate metastasis, as a basis for developing agents that inhibit this process. Toward this goal, we recently demonstrated that intercellular adhesion molecule-2 (ICAM-2) converted neuroblastoma (NB) cells from a metastatic to a non-metastatic phenotype, a previously unknown function for ICAM-2. Interestingly, ICAM-2 suppressed metastatic but not tumorigenic potential in preclinical models, supporting a novel mechanism of regulating metastasis. We hypothesized that the effects of ICAM-2 on NB cell phenotype depend on the interaction of ICAM-2 with the cytoskeletal linker protein α-actinin. The goal of the study presented here was to evaluate the impact of α-actinin binding to ICAM-2 on the phenotype of NB tumor cells. We used in silico approaches to examine the likelihood that the cytoplasmic domain of ICAM-2 binds directly to α-actinin. We then expressed variants of ICAM-2 with mutated α-actinin-binding domains, and compared the impact of ICAM-2 and each variant on NB cell adhesion, migration, anchorage-independent growth, co-precipitation with α-actinin and production of localized and disseminated tumors in vivo. The in vitro and in vivo characteristics of cells expressing ICAM-2 variants with modified α-actinin-binding domains differed from cells expressing ICAM-2 wild type (WT) and also from cells that expressed no detectable ICAM-2. Like the WT protein, ICAM-2 variants inhibited cell adhesion, migration and colony growth in vitro. However, unlike the WT protein, ICAM-2 variants did not completely suppress development of disseminated NB tumors in vivo. The data suggest the presence of α-actinin-dependent and α-actinin-independent mechanisms, and indicate that the interaction of ICAM-2 with α-actinin is critical to conferring an ICAM-2-mediated non-metastatic phenotype in NB cells.

Dataset Information

ICAM-5 affects spine maturation by regulation of NMDA receptor binding to ?-actinin.

Publications

ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin.

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