A membrane-targeting signal in the amino terminus of the neuronal protein GAP-43

Zuber, Mauricio X.; Strittmatter, Stephen M.; Fishman, Mark C.

doi:10.1038/341345a0

Cited by 179 publications

(110 citation statements)

References 31 publications

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“…The protein was subsequently shown to be palmitoylated at Cys-3 and Cys-4, and mutation of these residues to either threonine or glycine eliminated the binding of GAP-43 to membranes [55,106]. The N-terminal 20 amino acids of GAP-43 in rat corresponds to MLCCM RRTKQVEKNDEDQKI [7].…”

Section: Palmitoylation and Basic Residues Are Required For The Initimentioning

confidence: 99%

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Denny

2006

202

166

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GAP-43 is an intracellular growth-associated protein that appears to assist neuronal pathfinding and branching during development and regeneration, and may contribute to presynaptic membrane changes in the adult, leading to the phenomena of neurotransmitter release, endocytosis and synaptic vesicle recycling, long-term potentiation, spatial memory formation, and learning. GAP-43 becomes bound via palmitoylation and the presence of three basic residues to membranes of the early secretory pathway. It is then sorted onto vesicles at the late secretory pathway for fast axonal transport to the growth cone or presynaptic plasma membrane. The palmitate chains do not serve as permanent membrane anchors for GAP-43, because at steady-state most of the GAP-43 in a cell is membrane-bound but is not palmitoylated. Filopodial extension and branching take place when GAP-43 is phosphorylated at Ser-41 by protein kinase C, and this occurs following neurotrophin binding and the activation of numerous small GTPases. GAP-43 has been proposed to cluster the acidic phospholipid phosphatidylinositol 4,5-bisphosphate in plasma membrane rafts. Following GAP-43 phosphorylation, this phospholipid is released to promote local actin filament-membrane attachment. The phosphorylation also releases GAP-43 from calmodulin. The released GAP-43 may then act as a lateral stabilizer of actin filaments. N-terminal fragments of GAP-43, containing 10-20 amino acids, will activate heterotrimeric G proteins, direct GAP-43 to the membrane and lipid rafts, and cause the formation of filopodia, possibly by causing a change in membrane tension. This review will focus on new information regarding GAP-43, including its binding to membranes and its incorporation into lipid rafts, its mechanism of action, and how it affects and is affected by extracellular agents.

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Section: Palmitoylation and Basic Residues Are Required For The Initimentioning

confidence: 99%

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Denny

2006

202

166

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“…Studies on the neuronal proteins GAP-43 and paralemmin show that palmitoylation is important for localizing these proteins to filopodia (Zuber et al, 1989a(Zuber et al, , 1989bKutzleb et al, 1998). In contrast, dual palmitoylation of PSD-95 is necessary for appropriate postsynaptic localization to dendritic spines (Craven et al, 1999;El-Husseini et al, 2000;El-Husseini and Bredt, 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs

Gauthier-Campbell

Bredt

Murphy

et al. 2004

MBoC

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Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes. INTRODUCTIONNeurons possess an elaborate plasma membrane architecture that includes axons, dendrites, and synaptic sites (Da Silva and Dotti, 2002). Modulation of the plasma membrane shape and composition regulate processes outgrowth, axonal development, dendritic branching, and the construction of synapses (Jontes and Smith, 2000). These changes are regulated by interactions between the constituents of the plasma membrane, the exo/endocytic vesicles, and the cytoskeleton (Wood and Martin, 2002). In nonneuronal cells, differential modulation of membrane flow can result in the formation of processes such as microspikes, lamellopodia, and filopodia (Wood and Martin, 2002). However, factors that regulate the formation and maintenance of specific classes of membranous processes in neuronal cells remain poorly understood.Dendritic filopodia, cell surface extensions filled with tight parallel bundles of actin filaments, are thought to be precursors for developing synapses (Dailey and Smith, 1996;Small, 1988). Filopodia are typically 5-35 m in length and rapidly alter their position and shape. In developing axons, filopodia occur at the tips of growth cones and may aid the axon in finding its appropriate target. In dendrites, filopodia act as precursors to spines, short bulbous protrusions of the dendrite that form excitatory postsynaptic contacts on many neurons (Jontes and Smith, 2000). Thus, changes in membrane structure that result in the formation of filopodia are likely important in axonal guidance and spine formation. In contrast, dendritic branching is thought to be mediated via an actin and/or microtubule-dependent mechanisms (Jan and Jan, 2003). Recent studies showed that in early neuronal development dendrites originate from lamellopodia and short neurites (Jan and Jan, ...

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“…The amino terminus, corresponding to the coding region of exon 1, is crucial to membrane binding (Zuber et al, 1989b), and to G-protein stimulation (Strittmatter et al, 1990(Strittmatter et al, , 1994a. Both functions depend upon the two cysteines (Zuber et al, 1989b;Strittmatter et al, 1990), which are palmitoylated (Sudo et al, 1992), although how much GAP-43 is depalmitoylated under different situations is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Both functions depend upon the two cysteines (Zuber et al, 1989b;Strittmatter et al, 1990), which are palmitoylated (Sudo et al, 1992), although how much GAP-43 is depalmitoylated under different situations is not clear. to the amino terminus stimulate isolated G,,, although less effectively than does native GAP-43 (Strittmatter et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…It has several functional domains, encoded in three exons. The first exon encodes a membrane binding and G protein stimulating region (Zuber et al, 1989b;Strittmatter et al, 1990). The second exon includes a calmodulin binding site, unusual in that its affinity for calmodulin is reduced by increased calcium levels and by phosphorylation of an adjacent serine by protein kinase C (Alexander et al, 1987).…”

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confidence: 99%

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Ligand-induced growth cone collapse: amplification and blockade by variant GAP-43 peptides

Igarashi

Sudo

et al. 1995

J. Neurosci.

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Growth cones are powerful amplifiers for signals from the microenvironment. Their collapse can be triggered by cell surface components of myelin and brain membranes, as well as by soluble ligands, including neurotransmitters. GAP-43 is a protein concentrated on the inner surface of the growth cone membrane. Assayed in isolation, it interacts with the heterotrimeric protein, G(o), and in oocytes it amplifies the effects of ligand-triggered G protein activation. We wished to examine whether GAP-43 serves to amplify signals at the growth cone. The G(o) stimulating region of GAP-43 is encoded in the 10 amino acids (MLCCMRRT-KQ) of the first exon. We examined the effect of this peptide upon chick dorsal root ganglion growth cone collapse and neurite retraction triggered by brain membranes or myelin, as well as by serotonin. We find that application of the GAP-43 1–10 peptide amplifies the effects of all three ligands. The amplification is greater when GAP-43 1–10 is injected intracellularly. Peptides with amino acid substitutions for the two cysteine residues manifest parallel changes in growth cone collapse and G(o) stimulation. In particular, tyrosine or methionine substitutions cause the peptide to inhibit G(o) and to block induced growth cone collapse. The GAP-43 peptides therefore regulate the sensitivity of growth cones to extrinsic signals. The modified peptides serve as a starting point for the design of reagents to enhance CNS regeneration.

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A membrane-targeting signal in the amino terminus of the neuronal protein GAP-43

Cited by 179 publications

References 31 publications

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs

Ligand-induced growth cone collapse: amplification and blockade by variant GAP-43 peptides

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