Abstract
Scaffolding protein 4.1N is a neuron-enriched 4.1 homologue. 4.1N contains three conserved domains, including the N-terminal 4.1-ezrin-radixin-moesin (FERM) domain, internal spectrin–actin–binding (SAB) domain, and C-terminal domain (CTD). Interspersed between the three domains are nonconserved domains, including U1, U2, and U3. The role of 4.1N was first reported in the nerve system. Then, extensive studies reported the role of 4.1N in cancers and other diseases. 4.1N performs numerous vital functions in signaling transduction by interacting, locating, supporting, and coordinating different partners and is involved in the molecular pathogenesis of various diseases. In this review, recent studies on the interactions between 4.1N and its contactors (including the α7AChr, IP3R1, GluR1/4, GluK1/2/3, mGluR8, KCC2, D2/3Rs, CASK, NuMA, PIKE, IP6K2, CAM 1/3, βII spectrin, flotillin-1, pp1, and 14-3-3) and the 4.1N-related biological functions in the nerve system and cancers are specifically and comprehensively discussed. This review provides critical detailed mechanistic insights into the role of 4.1N in disease relationships.
Highlights
Neuron-enriched protein 4.1N and three other homologues (4.1R, 4.1B, and 4.1G) belong to the protein 4.1 family
4.1N and K-Cl co-transporter 2 (KCC2) are highly expressed during the early development of neurons (Walensky et al, 1999; Gulyás et al, 2001; Ludwig et al, 2003). 4.1N in conjunction with KCC2 is significantly correlated with the maturation of excitatory synapses (Rivera et al, 1999; Li et al, 2007). 4.1N is a link between KCC2 and the dendritic spine cytoskeleton, and the N-terminal 4.1-ezrin-radixin-moesin (FERM) domain of 4.1N and the C-terminal domain (CTD) of KCC2 are critical for mediating the direct interaction between 4.1N and KCC2 (Li et al, 2007)
Protein 4.1s–nuclear mitotic apparatus (NuMA) interactions are required for NuMA cortical stability and spindle orientation integrity and stretch-induced spindle reorientation (Seldin et al, 2013). 4.1N directly contracts with protein NuMA through the CTD (679–879 residues). 4.1N acts as an antiproliferative mediator of nerve growth factor (NGF) by antagonizing the role of NuMA in mitosis in PC12 cells
Summary
Neuron-enriched protein 4.1N and three other homologues (4.1R, 4.1B, and 4.1G) belong to the protein 4.1 family. The CTD overexpression of 4.1N and 4.1G or disruption of the F-action network leads to reduced plasma membrane GluR1 both in heterologous cells and cultured neurons, suggesting that the proteins 4.1N and 4.1G act as a link between AMPARs and the actin cytoskeleton, through which 4.1N anchors AMPARs to the actin cytoskeleton (Coleman et al, 2003), stabilizes AMPAR expression on the excitatory synapse surface (Coleman et al, 2003), and contributes to synaptic plasticity (Lin et al, 2009). Synapse-associated protein-97 (SAP97) regulates the synaptic localization of AMPARs. 4.1N potentially binds SAP97 isoforms containing the I3 domain. CAM1 is an important molecule during early synaptogenesis, and 4.1N is a specific CAM1 effector for AMPAR recruitment during synapse formation (Hoy et al, 2009)
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