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Kidins220/ARMS As a Functional Mediator of Multiple Receptor Signalling Pathways

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Kidins220/ARMS As a Functional Mediator of Multiple Receptor Signalling Pathways Commentary 1845 Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways Veronika E. Neubrand1,*, Fabrizia Cesca2,*, Fabio Benfenati2 and Giampietro Schiavo3,` 1Instituto de Parasitologı´a y Biomedicina Lo´pez-Neyra, IPBLN-CSIC, Avda. Conocimiento S/N, 18100 Armilla, Granada, Spain 2Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy 3Molecular Neuropathology Laboratory Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK *These authors contributed equally to this work `Author for correspondence ([email protected]) Journal of Cell Science 125, 1845–1854 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.102764 Summary An increasing body of evidence suggests that several membrane receptors – in addition to activating distinct signalling cascades – also engage in substantial crosstalk with each other, thereby adjusting their signalling outcome as a function of specific input information. However, little is known about the molecular mechanisms that control their coordination and integration of downstream signalling. A protein that is likely to have a role in this process is kinase-D-interacting substrate of 220 kDa [Kidins220, also known as ankyrin repeat- rich membrane spanning (ARMS), hereafter referred to as Kidins220/ARMS]. Kidins220/ARMS is a conserved membrane protein that is preferentially expressed in the nervous system and interacts with the microtubule and actin cytoskeleton. It interacts with neurotrophin, ephrin, vascular endothelial growth factor (VEGF) and glutamate receptors, and is a common downstream target of several trophic stimuli. Kidins220/ARMS is required for neuronal differentiation and survival, and its expression levels modulate synaptic plasticity. Kidins220/ARMS knockout mice show developmental defects mainly in the nervous and cardiovascular systems, suggesting a crucial role for this protein in modulating the cross talk between different signalling pathways. In this Commentary, we summarise existing knowledge regarding the physiological functions of Kidins220/ARMS, and highlight some interesting directions for future studies on the role of this protein in health and disease. Key words: Kidins220/ARMS, Neuronal differentiation, Neurotrophins, RTK signalling, Synaptic plasticity Introduction The vast majority of these ligands perform their physiological Journal of Cell Science The correct development of the nervous system relies on functions through plasma membrane receptors that have tyrosine the ability of axons and dendrites to recognise their targets. kinase activity – the receptor tyrosine kinases (RTKs) – which During this highly regulated process, neurons migrate and form results in distinct signalling outputs and cellular effects. functional connections in response to gradients of growth factors However, how RTKs mediate such diverse biological that regulate multiple neuronal functions, including cell outcomes by starting from a common subset of signalling survival, differentiation and synaptic plasticity (Bibel and molecules – such as the Ras protein family, the extracellular Barde, 2000; Chao, 2003; Huang and Reichardt, 2003). The regulated kinases (ERKs; also known as mitogen activated neurotrophin (NT) family is one of the best-characterised groups protein kinases, MAPKs), Akt and phospholipase Cc (PLCc)– of neurotrophic factors and includes nerve growth factor (NGF), is presently unclear. The signal specificity of NT receptors is brain derived neurotrophic factor (BDNF), and neurotrophin-3 tuned by a number of factors, including the repertoire of Trk (NT3) and -4 (NT4, also known as NT4/5) (Huang and receptors and the level of p75NTR expressed by a particular Reichardt, 2001). Neurotrophins bind with high affinity to neuron, which determine the subset of neurotrophins to which a three related tropomyosin receptor kinases (Trks): NGF binds particular neuron would respond (Clary and Reichardt, 1994; mainly to TrkA, whereas BDNF and NT4/5 bind mainly to Strohmaier et al., 1996; Hapner et al., 1998; Palko et al., 1999; TrkB, and NT3 to TrkC. In addition, all neurotrophins also bind Stoilov et al., 2002). Upon binding of NTs, Trk receptors dimerise to the p75 neurotrophin receptor (p75NTR, also known as and cross-phosphorylate each other. Activated Trk receptors are NGFR), a member of the tumour necrosis factor (TNF)-receptor then able to recruit a number of adaptors through their superfamily (Bibel and Barde, 2000). Other growth factors that phosphorylated residues. At the intracellular level, availability of are paramount in neuronal growth and development are the different substrates or adaptors could, thus, control signalling glial-cell-line-derived neurotrophic factor (GDNF), which acts downstream of Trk receptors (Lee et al., 2001). Additionally, the through the Ret tyrosine kinase receptor, and the GDNF family response to neurotrophin signals depends on the temporal and receptor a (GFRa) (Paratcha and Ledda, 2008). In addition, spatial pattern of stimulation. Thus, transient or sustained trophic factors such as the VEGF and the ephrin–ephrin-receptor activation of the MAPK, phosphoinositide kinase-3 (PI3K) or (ephrin–Eph) families have crucial roles both inside and outside Akt pathways mediates distinct cellular effects, for example by the nervous system (Klein, 2009; Ruiz de Almodovar et al., promoting a local and fast response at the growth cone 2009). compared with a slower response at distal sites, such as the 1846 Journal of Cell Science 125 (8) soma (Marshall, 1995; Kuruvilla et al., 2000; Watson et al., Kidins220/ARMS is a multifunctional scaffolding protein 2001). To add a further level of complexity, different receptors Kidins220/ARMS was initially identified as a substrate for can interact with each other. For example, p75NTR is found in protein kinase D (PKD) in neural cells (Iglesias et al., 2000), and complex with Trk, sortilin-1 (Sorl1) or Nogo (RTN4R) receptors independently characterised as a downstream target of the (Bronfman and Fainzilber, 2004), whereas TrkB interacts with signalling mediated by neurotrophins and ephrins (Kong et al., ephrin-A7 and EphA5 (Fitzgerald et al., 2008; Marler et al., 2001). Kidins220/ARMS is an integral membrane protein, 2008). Similarly, GDNFaR, Ret tyrosine kinase and containing four transmembrane segments in the central part of protocadherins cooperate to regulate neuronal survival the molecule, and N- and C-terminal tails both exposed to the (Schalm et al., 2010), and the interaction between EphB and cytoplasm (Fig. 1). Sequence analysis of Kidins220/ARMS N-methyl-D-aspartate (NMDA) receptors – an important class revealed the presence of numerous domains that mediate of glutamate receptors – is crucial for the modulation of synaptic protein–protein interactions. The N-terminus of Kidins220/ plasticity (Dalva et al., 2000; Henderson et al., 2001). Thus, a ARMS contains eleven ankyrin repeats (residues 37–398 in the complex interplay between the repertoire of receptors and the mouse sequence), which form a concave binding surface that is availability of downstream effectors ultimately determines the accessible to molecular partners, such as the Rho–guanine response of a neuron to a given stimulus. nucleotide exchange factor (RhoGEF) Trio (Neubrand et al., A common downstream effector of these pathways is the 2010). Kidins220/ARMS has been included in the Kidins220/ scaffolding protein Kidins220/ARMS. In mice, embryos that lack ARMS and PifA (KAP) family of P-loop nucleotide phosphatases Kidins220/ARMS die at birth, indicating that this protein is (NTPases). P-loop NTPases contain Walker A and Walker B essential for life. In addition to a variety of neuronal phenotypes, motifs (WA and WB, respectively) (Higgins et al., 1988), which these embryos show severe defects in vascular development and are often involved in the binding of nucleotides and have been cardiac malformations, which are likely to be the cause of death identified in the juxtamembrane regions flanking the N- and C- (Cesca et al., 2011; Cesca et al., 2012). Mutants of Kidins220/ terminus of Kidins220/ARMS. Members of this family are ARMS have been described in Caenorhabditis elegans (tag-114) predicted to mediate the assembly of protein complexes that are and Drosophila melanogaster (Dmel\CG42672) (see also http:// associated with the inner surface of cell membranes (Aravind www.wormbase.org/ and http://flybase.org/). However, only a et al., 2004). Interestingly, Kidins220/ARMS binds ATP partial phenotypic characterisation of these mutants has been (Teresa Iglesias and G.S., unpublished), although a functional provided so far, making the analysis performed in mice the most role for its Walker motifs has so far not been established. Thus, informative to date. further work is required to establish whether Kidins220/ARMS NT VEGF ephrin-A1 Journal of Cell Science Glut VEGFRs p75NTR NMDAR Trks AMPAR EphA4 α-syntrophin S-SCAM Neuronal survival and/or K891 Vascular death upon excitotoxicity PKD S919 Trk signalling development from endosomes Jak–Stat signalling Exit from TGN Y1096 SCG10 Localisation Kinesin-1 Synapse development SCLIP to lipid rafts CrkL MAP1a, 1b, 2 Trio Sustained MAPK activation MT cytoskeleton Connection to actin Neuronal differentiation and MT cytoskeleton Key Walker A, B KIM Caspase-3 site Transmembrane region Proline-rich domain PDZ-binding motif Ubiquitylation site Ankyrin repeat SAM domain
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