Gap-43 protein explained

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.

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 intellectually disabled.^{[8] [9]}

Further reading

• Fantini F, Johansson O . Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: a comparative immunohistochemical investigation . The Journal of Investigative Dermatology . 99 . 6 . 734–42 . Dec 1992 . 1281863 . 10.1111/1523-1747.ep12614465 .
• Mercken M, Lübke U, Vandermeeren M, Gheuens J, Oestreicher AB . Immunocytochemical detection of the growth-associated protein B-50 by newly characterized monoclonal antibodies in human brain and muscle . Journal of Neurobiology . 23 . 3 . 309–21 . Apr 1992 . 1385623 . 10.1002/neu.480230310 .
• Spencer SA, Schuh SM, Liu WS, Willard MB . GAP-43, a protein associated with axon growth, is phosphorylated at three sites in cultured neurons and rat brain . The Journal of Biological Chemistry . 267 . 13 . 9059–64 . May 1992 . 10.1016/S0021-9258(19)50388-X . 1533624 . free .
• Apel ED, Litchfield DW, Clark RH, Krebs EG, Storm DR . Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin . The Journal of Biological Chemistry . 266 . 16 . 10544–51 . Jun 1991 . 10.1016/S0021-9258(18)99258-6 . 1828073 . free .
• Apel ED, Byford MF, Au D, Walsh KA, Storm DR . Identification of the protein kinase C phosphorylation site in neuromodulin . Biochemistry . 29 . 9 . 2330–5 . Mar 1990 . 2140056 . 10.1021/bi00461a017 .
• Kosik KS, Orecchio LD, Bruns GA, Benowitz LI, MacDonald GP, Cox DR, Neve RL . Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human . Neuron . 1 . 2 . 127–32 . Apr 1988 . 3272162 . 10.1016/0896-6273(88)90196-1 . 12067138 .
• Ng SC, de la Monte SM, Conboy GL, Karns LR, Fishman MC . Cloning of human GAP-43: growth association and ischemic resurgence . Neuron . 1 . 2 . 133–9 . Apr 1988 . 3272163 . 10.1016/0896-6273(88)90197-3 . 19627547 .
• Nielander HB, De Groen PC, Eggen BJ, Schrama LH, Gispen WH, Schotman P . Structure of the human gene for the neural phosphoprotein B-50 (GAP-43) . Brain Research. Molecular Brain Research . 19 . 4 . 293–302 . Sep 1993 . 8231732 . 10.1016/0169-328X(93)90128-C . 1874/4067 . free .
• Oehrlein SA, Parker PJ, Herget T . 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 . The Biochemical Journal . 317 . 1. 219–24 . Jul 1996 . 8694767 . 1217466 . 10.1042/bj3170219. 317 .
• Kanazir S, Ruzdijic S, Vukosavic S, Ivkovic S, Milosevic A, Zecevic N, Rakic L . GAP-43 mRNA expression in early development of human nervous system . Brain Research. Molecular Brain Research . 38 . 1 . 145–55 . May 1996 . 8737678 . 10.1016/0169-328X(96)00008-3 .
• de Groen PC, Eggen BJ, Gispen WH, Schotman P, Schrama LH . Cloning and promoter analysis of the human B-50/GAP-43 gene . Journal of Molecular Neuroscience . 6 . 2 . 109–19 . 1996 . 8746449 . 10.1007/BF02736770 . 22911100 .
• Chao S, Benowitz LI, Krainc D, Irwin N . Use of a two-hybrid system to investigate molecular interactions of GAP-43 . Brain Research. Molecular Brain Research . 40 . 2 . 195–202 . Sep 1996 . 8872303 . 10.1016/0169-328X(96)00049-6 .
• Gamby C, Waage MC, Allen RG, Baizer L . Analysis of the role of calmodulin binding and sequestration in neuromodulin (GAP-43) function . The Journal of Biological Chemistry . 271 . 43 . 26698–705 . Oct 1996 . 8900147 . 10.1074/jbc.271.43.26698 . free .
• Heuss D, Schlötzer-Schrehardt U . Subcellular localization of phosphoprotein B-50 in regenerating muscle. An immuno-electron microscopic study . Neurological Research . 20 . 4 . 360–4 . Jun 1998 . 9618702 . 10.1080/01616412.1998.11740532.
• Neve RL, Coopersmith R, McPhie DL, Santeufemio C, Pratt KG, Murphy CJ, Lynn SD . The neuronal growth-associated protein GAP-43 interacts with rabaptin-5 and participates in endocytosis . The Journal of Neuroscience . 18 . 19 . 7757–67 . Oct 1998 . 9742146 . 6793001 . 10.1523/JNEUROSCI.18-19-07757.1998.
• Arni S, Keilbaugh SA, Ostermeyer AG, Brown DA . Association of GAP-43 with detergent-resistant membranes requires two palmitoylated cysteine residues . The Journal of Biological Chemistry . 273 . 43 . 28478–85 . Oct 1998 . 9774477 . 10.1074/jbc.273.43.28478 . free .
• Eastwood SL, Harrison PJ . Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia . Neuroscience . 86 . 2 . 437–48 . Sep 1998 . 9881859 . 10.1016/S0306-4522(98)00040-2 . 41460546 .
• 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 . Characterization of single-nucleotide polymorphisms in coding regions of human genes . Nature Genetics . 22 . 3 . 231–8 . Jul 1999 . 10391209 . 10.1038/10290 . 195213008 .
• Riederer BM, Routtenberg A . Can GAP-43 interact with brain spectrin? . Brain Research. Molecular Brain Research . 71 . 2 . 345–8 . Aug 1999 . 10521589 . 10.1016/S0169-328X(99)00179-5 .
• Vento P, Soinila S . Quantitative comparison of growth-associated protein GAP-43, neuron-specific enolase, and protein gene product 9.5 as neuronal markers in mature human intestine . The Journal of Histochemistry and Cytochemistry . 47 . 11 . 1405–16 . Nov 1999 . 10544214 . 10.1177/002215549904701107 . free .

External links

• • ihop-net, Growth associated protein 43
• NCBI

Notes and References

1. Kosik KS, Orecchio LD, Bruns GA, Benowitz LI, MacDonald GP, Cox DR, Neve RL . Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human . Neuron . 1 . 2 . 127–32 . Apr 1988 . 3272162 . 10.1016/0896-6273(88)90196-1 . 12067138 .
2. Referenced within : Rosskothen-Kuhl N, Illing RB . 2014 . Gap43 Transcription Modulation in the Adult Brain Depends on Sensory Activity and Synaptic Cooperation . 10.1371/journal.pone.0092624 . 24647228 . PLOS ONE . 9 . 3. e92624 . 3960265 . 2014PLoSO...992624R . free .
3. Web site: Entrez Gene: GAP43 growth associated protein 43.
4. Benowitz LI, Routtenberg A . GAP-43: an intrinsic determinant of neuronal development and plasticity . Trends in Neurosciences . 20 . 2 . 84–91 . Feb 1997 . 9023877 . 10.1016/S0166-2236(96)10072-2 . 35082372 .
5. Book: Aarts LH, Schotman P, Verhaagen J, Schrama LH, Gispen WH . The Role of the Neural Growth Associated Protein B-50/Gap-43 in Morphogenesis . Advances in Experimental Medicine and Biology . Molecular and Cellular Mechanisms of Neuronal Plasticity . 446 . 85–106 . 1998 . 10079839 . 10.1007/978-1-4615-4869-0_6 . 978-1-4613-7209-7 .
6. Mishra R, ManiS . GAP-43 is key to mitotic spindle control and centrosome-based polarization in neurons.. Cell Cycle . 7 . 3. 348–357 . 2008 . 10.4161/cc.7.3.5235. 18235238. free.
7. Benowitz LI, Routtenberg A . A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity . Trends in Neurosciences . 10 . 12. 527–532 . 1987 . 10.1016/0166-2236(87)90135-4 . 54322365 .
8. Genuardi M, Calvieri F, Tozzi C, Coslovi R, Neri G . A new case of interstitial deletion of chromosome 3q, del(3q)(q13.12q21.3), with agenesis of the corpus callosum . Clinical Dysmorphology . 3 . 4 . 292–6 . Oct 1994 . 7894733 . 10.1097/00019605-199410000-00003 . 38716384 .
9. Mackie Ogilvie C, Rooney SC, Hodgson SV, Berry AC . Deletion of chromosome 3q proximal region gives rise to a variable phenotype . Clinical Genetics . 53 . 3 . 220–2 . Mar 1998 . 9630079 . 10.1111/j.1399-0004.1998.tb02681.x . 20499346 .