请输入您要查询的百科知识：

　

词条 Gap-43 protein
释义

  1. Synonyms

  2. Function

  3. Clinical significance

  4. Model organisms

  5. References

  6. Further reading

  7. External links

{{Infobox_gene}}

Growth Associated Protein 43 (GAP43) is a protein encoded by the GAP43 gene[1] in humans.

GAP43 is called a "growth" or "plasticity" protein because it is expressed at high levels in neuronal growth cones during development[2] and axonal regeneration, and it is phosphorylated after long-term potentiation and after learning.{{citation needed|date=December 2018}}

GAP43 is a crucial component of the axon and presynaptic terminal. Its null mutation leads to death within days after birth, due to axon pathfinding defects.[3]

Synonyms

GAP43 is also referred to as:

  • protein F1
  • neuromodulin
  • neural phosphoprotein B-50
  • axonal membrane protein GAP-43
  • calmodulin-binding protein P-57
  • nerve growth-related peptide GAP43
  • neuron growth-associated protein 43

Function

GAP43, is a nervous tissue-specific cytoplasmic protein that can be attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4. This sequence targets GAP43 to lipid rafts. It is a major protein kinase C (PKC) substrate and is considered to play a key role in neurite formation, regeneration, and plasticity.[4][5] The role of GAP-43 in CNS development is not limited to effects on axons: It is also a component of the centrosome, and differentiating neurons that do not express GAP-43 show mislocalization of the centrosome and mitotic spindles, particularly in neurogenic cell divisions. As a consequence, in the cerebellum, the neuronal precursor pool fails to expand normally and the cerebellum is significantly smaller. [6]

Several different laboratories studying the same protein, now called GAP43, initially used different names. It was designated F1, then B-50, then GAP43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule.[7] F1 was localized to synapses, and was increased in its phosphorylation one day after learning. However, F1 was not cAMP kinase dependent. B-50 was regulated by the pituitary peptide ACTH and was associated with grooming behavior. In the case of GAP-43, it was designated as a growth-associated protein because its synthesis was upregulated during axonal regeneration. Pp46 was concentrated in neuronal growth cones and was thus postulated to play an important role in brain development. In the case of neuromodulin, it was shown to bind calmodulin avidly.

GAP43, the consensus choice for its designation,[7] is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4, though it can exist in the non-bound form in the cytoplasm. This dual sequence enables the association of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] or PIP2, with actin, facilitating the latter’s polymerization thereby regulating neuronal structure. This can occur within a lipid raft so as to compartmentalize and localize motility of filopodia in growth cones in developing brains, and could also remodel presynaptic terminals in adults in an activity-dependent manner. GAP-43 is also a protein kinase C (PKC) substrate. Phosphorylation of serine-41 on GAP-43 by PKC regulates neurite formation, regeneration, and synaptic plasticity.[4]

Because of the association and potential binding of GAP43 with a number of different molecules, including PKC, PIP2, actin, calmodulin, spectrin, palmitate, synaptophysin, amyloid and tau protein, it may be useful to think of GAP43 as an adaptor protein situated within the terminal in a supramolecular complex regulating presynaptic terminal functions, particularly bidirectional communication with the postsynaptic process. Its important role in memory and information storage is executed through its cell biological mechanisms of phosphorylation, palmitoylation, protein-protein interaction and structural remodeling via actin polymerization.

Clinical significance

Humans with a deletion in one allele of the GAP43 gene fail to form telencephalic commissures and are mentally retarded.[8][9]

Model organisms

Model organisms have been used in the study of GAP43 function. A conditional knockout mouse line, called Gap43tm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and increased IgG1 levels were observed in these animals.[12]

Studies on another homozygous GAP43 knockout mouse line found it to be lethal days after birth because it plays a critical role in the development of the mammalian CNS.[20] Telencephalic commissures fail to form,[21] thalamocortical afferents are mistargeted, especially in somatosensory, particularly barrel, cortex.[20] GAP43 is not only important for axon targeting during development but it has been shown to be important also for the maintenance of the structure and dynamics of axonal fibres and of their synaptic terminals in wild-type rodents both during normal conditions and during lesion-induced axonal sprouting.[22][23][24] The cerebellum is also affected.[25] GAP43 is also haploinsufficient for the cortical phenotypes and the severity of the axon targeting phenotype is directly related to the extent to which the affected axons are phosphorylated by PKC, suggesting that axons require a functional threshold of phosphorylated GAP43 for targeting to occur normally.[21] Moreover, elevation above this threshold in GAP43 mice can enhance learning and also facilitate a physiological model of learning, long-term potentiation (LTP).[26] However, further enrichment beyond a certain level can be devastating to cognitive functions.{{Citation needed|reason=Reliable source needed for the whole sentence|date=March 2016}}

References

1. ^{{cite journal | vauthors = Kosik KS, Orecchio LD, Bruns GA, Benowitz LI, MacDonald GP, Cox DR, Neve RL | title = Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human | journal = Neuron | volume = 1 | issue = 2 | pages = 127–32 | date = Apr 1988 | pmid = 3272162 | doi = 10.1016/0896-6273(88)90196-1 }}
2. ^Referenced within : Rosskothen-Kuhl, Nicole, and Robert-Benjamin Illing. 2014. “Gap43 Transcription Modulation in the Adult Brain Depends on Sensory Activity and Synaptic Cooperation” ed. Berta Alsina. PLoS ONE 9(3): e92624. http://dx.plos.org/10.1371/journal.pone.0092624.
3. ^{{cite web | title = Entrez Gene: GAP43 growth associated protein 43| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2596| accessdate = }}
4. ^1 {{cite journal | vauthors = Benowitz LI, Routtenberg A | title = GAP-43: an intrinsic determinant of neuronal development and plasticity | journal = Trends in Neurosciences | volume = 20 | issue = 2 | pages = 84–91 | date = Feb 1997 | pmid = 9023877 | doi = 10.1016/S0166-2236(96)10072-2 }}
5. ^{{cite book | vauthors = Aarts LH, Schotman P, Verhaagen J, Schrama LH, Gispen WH | title = The role of the neural growth associated protein B-50/GAP-43 in morphogenesis | journal = Advances in Experimental Medicine and Biology | volume = 446 | issue = | pages = 85–106 | year = 1998 | pmid = 10079839 | doi = 10.1007/978-1-4615-4869-0_6 | isbn = 978-1-4613-7209-7 }}
6. ^{{cite journal | vauthors =Mishra R, ManiS | title = GAP-43 is key to mitotic spindle control and centrosome-based polarization in neurons.| journal =Cell Cycle | volume = 7 | issue = 3| pages =348–357 | year = 2008 | month = | doi = 10.4161/cc.7.3.5235| pmid = 18235238| url = }}
7. ^1 {{cite journal | vauthors = Benowitz LI, Routtenberg A | title = A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity | journal =Trends in Neurosciences | volume = 10 | issue = 12| pages = 527–532 | year = 1987 | month = | doi = 10.1016/0166-2236(87)90135-4 | url = }}
8. ^{{cite journal | vauthors = Genuardi M, Calvieri F, Tozzi C, Coslovi R, Neri G | title = A new case of interstitial deletion of chromosome 3q, del(3q)(q13.12q21.3), with agenesis of the corpus callosum | journal = Clinical Dysmorphology | volume = 3 | issue = 4 | pages = 292–6 | date = Oct 1994 | pmid = 7894733 | doi = 10.1097/00019605-199410000-00003 }}
9. ^{{cite journal | vauthors = Mackie Ogilvie C, Rooney SC, Hodgson SV, Berry AC | title = Deletion of chromosome 3q proximal region gives rise to a variable phenotype | journal = Clinical Genetics | volume = 53 | issue = 3 | pages = 220–2 | date = Mar 1998 | pmid = 9630079 | doi = 10.1111/j.1399-0004.1998.tb02681.x }}
10. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBSD/salmonella-challenge/ |title=Salmonella infection data for Gap43 |publisher=Wellcome Trust Sanger Institute}}
11. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBSD/citrobacter-challenge/ |title=Citrobacter infection data for Gap43 |publisher=Wellcome Trust Sanger Institute}}
12. ^1 2 {{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | author = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages = 925–7 }}
13. ^Mouse Resources Portal, Wellcome Trust Sanger Institute.
14. ^{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Gap43 |title=International Knockout Mouse Consortium}}
15. ^{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4431861 |title=Mouse Genome Informatics}}
16. ^{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}
17. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}
18. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}
19. ^{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}
20. ^1 {{cite journal | vauthors = Strittmatter SM, Fankhauser C, Huang PL, Mashimo H, Fishman MC | title = Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43 | journal = Cell | volume = 80 | issue = 3 | pages = 445–52 | date = Feb 1995 | pmid = 7859286 | doi = 10.1016/0092-8674(95)90495-6 | url = http://linkinghub.elsevier.com/retrieve/pii/0092-8674(95)90495-6 }}
21. ^1 {{cite journal | vauthors = Shen Y, Mani S, Donovan SL, Schwob JE, Meiri KF | title = Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system | journal = The Journal of Neuroscience | volume = 22 | issue = 1 | pages = 239–47 | date = Jan 2002 | pmid = 11756507 | doi = 10.1523/JNEUROSCI.22-01-00239.2002}}
22. ^{{cite journal | vauthors = Grasselli G, Mandolesi G, Strata P, Cesare P | title = Impaired sprouting and axonal atrophy in cerebellar climbing fibres following in vivo silencing of the growth-associated protein GAP-43 | journal = PLOS ONE | volume = 6 | issue = 6 | pages = e20791 | date = June 2011 | pmid = 21695168 | doi = 10.1371/journal.pone.0020791 | pmc=3112224}}
23. ^{{cite journal | vauthors = Grasselli G, Strata P | title = Structural plasticity of climbing fibers and the growth-associated protein GAP-43 | journal = Frontiers in Neural Circuits | volume = 7 | issue = 25 | pages = 25 | date = February 2013 | pmid = 23441024 | doi = 10.3389/fncir.2013.00025 | pmc=3578352}}
24. ^{{cite journal | vauthors = Allegra Mascaro AL, Cesare P, Sacconi L, Grasselli G, Mandolesi G, Maco B, Knott GW, Huang L, De Paola V, Strata P, Pavone FS | title = In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 26 | pages = 10824–9 | date = Jun 2013 | pmid = 23754371 | doi = 10.1073/pnas.1219256110 | url = http://www.pnas.org/content/early/2013/06/06/1219256110 | pmc=3696745}}
25. ^{{cite journal | vauthors = Shen Y, Mishra R, Mani S, Meiri KF | title = Both cell-autonomous and cell non-autonomous functions of GAP-43 are required for normal patterning of the cerebellum in vivo | journal = Cerebellum | volume = 7 | issue = 3 | pages = 451–66 | year = 2008 | pmid = 18777197 | doi = 10.1007/s12311-008-0049-5 | pmc = 4164963 }}
26. ^{{cite journal | vauthors = Routtenberg A, Cantallops I, Zaffuto S, Serrano P, Namgung U | title = Enhanced learning after genetic overexpression of a brain growth protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 13 | pages = 7657–62 | date = Jun 2000 | pmid = 10861025 | pmc = 16601 | doi = 10.1073/pnas.97.13.7657 }}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Fantini F, Johansson O | title = Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: a comparative immunohistochemical investigation | journal = The Journal of Investigative Dermatology | volume = 99 | issue = 6 | pages = 734–42 | date = Dec 1992 | pmid = 1281863 | doi = 10.1111/1523-1747.ep12614465 }}
  • {{cite journal | vauthors = Mercken M, Lübke U, Vandermeeren M, Gheuens J, Oestreicher AB | title = Immunocytochemical detection of the growth-associated protein B-50 by newly characterized monoclonal antibodies in human brain and muscle | journal = Journal of Neurobiology | volume = 23 | issue = 3 | pages = 309–21 | date = Apr 1992 | pmid = 1385623 | doi = 10.1002/neu.480230310 }}
  • {{cite journal | vauthors = Spencer SA, Schuh SM, Liu WS, Willard MB | title = GAP-43, a protein associated with axon growth, is phosphorylated at three sites in cultured neurons and rat brain | journal = The Journal of Biological Chemistry | volume = 267 | issue = 13 | pages = 9059–64 | date = May 1992 | pmid = 1533624 | doi = }}
  • {{cite journal | vauthors = Apel ED, Litchfield DW, Clark RH, Krebs EG, Storm DR | title = Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin | journal = The Journal of Biological Chemistry | volume = 266 | issue = 16 | pages = 10544–51 | date = Jun 1991 | pmid = 1828073 | doi = }}
  • {{cite journal | vauthors = Apel ED, Byford MF, Au D, Walsh KA, Storm DR | title = Identification of the protein kinase C phosphorylation site in neuromodulin | journal = Biochemistry | volume = 29 | issue = 9 | pages = 2330–5 | date = Mar 1990 | pmid = 2140056 | doi = 10.1021/bi00461a017 }}
  • {{cite journal | vauthors = Kosik KS, Orecchio LD, Bruns GA, Benowitz LI, MacDonald GP, Cox DR, Neve RL | title = Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human | journal = Neuron | volume = 1 | issue = 2 | pages = 127–32 | date = Apr 1988 | pmid = 3272162 | doi = 10.1016/0896-6273(88)90196-1 }}
  • {{cite journal | vauthors = Ng SC, de la Monte SM, Conboy GL, Karns LR, Fishman MC | title = Cloning of human GAP-43: growth association and ischemic resurgence | journal = Neuron | volume = 1 | issue = 2 | pages = 133–9 | date = Apr 1988 | pmid = 3272163 | doi = 10.1016/0896-6273(88)90197-3 }}
  • {{cite journal | vauthors = Nielander HB, De Groen PC, Eggen BJ, Schrama LH, Gispen WH, Schotman P | title = Structure of the human gene for the neural phosphoprotein B-50 (GAP-43) | journal = Brain Research. Molecular Brain Research | volume = 19 | issue = 4 | pages = 293–302 | date = Sep 1993 | pmid = 8231732 | doi = 10.1016/0169-328X(93)90128-C }}
  • {{cite journal | vauthors = Oehrlein SA, Parker PJ, Herget T | title = Phosphorylation of GAP-43 (growth-associated protein of 43 kDa) by conventional, novel and atypical isotypes of the protein kinase C gene family: differences between oligopeptide and polypeptide phosphorylation | journal = The Biochemical Journal | volume = 317 | issue = 1| pages = 219–24 | date = Jul 1996 | pmid = 8694767 | pmc = 1217466 | doi = 10.1042/bj3170219| series = 317 }}
  • {{cite journal | vauthors = Kanazir S, Ruzdijic S, Vukosavic S, Ivkovic S, Milosevic A, Zecevic N, Rakic L | title = GAP-43 mRNA expression in early development of human nervous system | journal = Brain Research. Molecular Brain Research | volume = 38 | issue = 1 | pages = 145–55 | date = May 1996 | pmid = 8737678 | doi = 10.1016/0169-328X(96)00008-3 }}
  • {{cite journal | vauthors = de Groen PC, Eggen BJ, Gispen WH, Schotman P, Schrama LH | title = Cloning and promoter analysis of the human B-50/GAP-43 gene | journal = Journal of Molecular Neuroscience | volume = 6 | issue = 2 | pages = 109–19 | year = 1996 | pmid = 8746449 | doi = 10.1007/BF02736770 }}
  • {{cite journal | vauthors = Chao S, Benowitz LI, Krainc D, Irwin N | title = Use of a two-hybrid system to investigate molecular interactions of GAP-43 | journal = Brain Research. Molecular Brain Research | volume = 40 | issue = 2 | pages = 195–202 | date = Sep 1996 | pmid = 8872303 | doi = 10.1016/0169-328X(96)00049-6 }}
  • {{cite journal | vauthors = Gamby C, Waage MC, Allen RG, Baizer L | title = Analysis of the role of calmodulin binding and sequestration in neuromodulin (GAP-43) function | journal = The Journal of Biological Chemistry | volume = 271 | issue = 43 | pages = 26698–705 | date = Oct 1996 | pmid = 8900147 | doi = 10.1074/jbc.271.43.26698 }}
  • {{cite journal | vauthors = Heuss D, Schlötzer-Schrehardt U | title = Subcellular localization of phosphoprotein B-50 in regenerating muscle. An immuno-electron microscopic study | journal = Neurological Research | volume = 20 | issue = 4 | pages = 360–4 | date = Jun 1998 | pmid = 9618702 | doi = }}
  • {{cite journal | vauthors = Neve RL, Coopersmith R, McPhie DL, Santeufemio C, Pratt KG, Murphy CJ, Lynn SD | title = The neuronal growth-associated protein GAP-43 interacts with rabaptin-5 and participates in endocytosis | journal = The Journal of Neuroscience | volume = 18 | issue = 19 | pages = 7757–67 | date = Oct 1998 | pmid = 9742146 | doi = 10.1523/JNEUROSCI.18-19-07757.1998}}
  • {{cite journal | vauthors = Arni S, Keilbaugh SA, Ostermeyer AG, Brown DA | title = Association of GAP-43 with detergent-resistant membranes requires two palmitoylated cysteine residues | journal = The Journal of Biological Chemistry | volume = 273 | issue = 43 | pages = 28478–85 | date = Oct 1998 | pmid = 9774477 | doi = 10.1074/jbc.273.43.28478 }}
  • {{cite journal | vauthors = Eastwood SL, Harrison PJ | title = Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia | journal = Neuroscience | volume = 86 | issue = 2 | pages = 437–48 | date = Sep 1998 | pmid = 9881859 | doi = 10.1016/S0306-4522(98)00040-2 }}
  • {{cite journal | vauthors = Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES | title = Characterization of single-nucleotide polymorphisms in coding regions of human genes | journal = Nature Genetics | volume = 22 | issue = 3 | pages = 231–8 | date = Jul 1999 | pmid = 10391209 | doi = 10.1038/10290 }}
  • {{cite journal | vauthors = Riederer BM, Routtenberg A | title = Can GAP-43 interact with brain spectrin? | journal = Brain Research. Molecular Brain Research | volume = 71 | issue = 2 | pages = 345–8 | date = Aug 1999 | pmid = 10521589 | doi = 10.1016/S0169-328X(99)00179-5 }}
  • {{cite journal | vauthors = Vento P, Soinila S | title = Quantitative comparison of growth-associated protein GAP-43, neuron-specific enolase, and protein gene product 9.5 as neuronal markers in mature human intestine | journal = The Journal of Histochemistry and Cytochemistry | volume = 47 | issue = 11 | pages = 1405–16 | date = Nov 1999 | pmid = 10544214 | doi = 10.1177/002215549904701107 }}
{{refend}}

External links

  • {{MeshName|Gap-43+protein}}
  • ihop-net, Growth associated protein 43
  • [https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=2596 NCBI]
{{Nerve tissue protein}}

1 : Genes mutated in mice
随便看

　

开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。

　

Copyright © 2023 OENC.NET All Rights Reserved
京ICP备2021023879号 更新时间：2024/11/11 9:44:02