SHANK2 explained

SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene.^{[1] [2]} Two alternative splice variants, encoding distinct isoforms, are reported. Additional splice variants exist but their full-length nature has not been determined.

Function

This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.^[2]

It is thought that SHANK2 might play a role in synaptogenesis by attaching metabotropic glutamate receptors (mGluRs) to an existing pool of NMDA receptors (NMDA-R), bylinking to the NMDA-R through PSD-95, and the mGluRs through HOMER1.^[3] An alternative hypothesis is that the Homer/Shank/GKAP/PSD-95 assembly mediates physical association of the NMDAR with IP3R/RYR and intracellular Ca2+ stores.

Interactions

SHANK2 has been shown to interact with:

• ARHGEF7,^[4]
• Cortactin,^[5]
• DLG4,^{[6] [7]}
• DLGAP1,^{[6] [7]} and
• DNM2.^[8]

Associations with neuropsychiatric disease

Mutations in SHANK2 have been associated with autism spectrum disorder (ASD) and schizophrenia.^[9] In particular, heterozygous loss-of-function mutations have a near-complete penetrance in ASD.^[10] Neurons generated from people with ASD and SHANK2 mutations develop larger dendritic trees and more synaptic connections than those from healthy controls.^[11] In addition, common mutations in SHANK2 have been linked to bipolar disorder.^[12]

Further reading

• Sheng M, Kim E . The Shank family of scaffold proteins . Journal of Cell Science . 113 (Pt 11) . 1851–6 . June 2000 . 10806096 . 113 . 11 . 10.1242/jcs.113.11.1851 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . 6 . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Du Y, Weed SA, Xiong WC, Marshall TD, Parsons JT . Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons . Molecular and Cellular Biology . 18 . 10 . 5838–51 . October 1998 . 9742101 . 109170 . 10.1128/MCB.18.10.5838 .
• Zitzer H, Richter D, Kreienkamp HJ . Agonist-dependent interaction of the rat somatostatin receptor subtype 2 with cortactin-binding protein 1 . The Journal of Biological Chemistry . 274 . 26 . 18153–6 . June 1999 . 10373412 . 10.1074/jbc.274.26.18153 . free .
• Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF . 6 . Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins . Neuron . 23 . 3 . 583–92 . July 1999 . 10433269 . 10.1016/S0896-6273(00)80810-7 . 16429070 . free .
• Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 6 . 3 . 197–205 . June 1999 . 10470851 . 10.1093/dnares/6.3.197 . free .
• Boeckers TM, Winter C, Smalla KH, Kreutz MR, Bockmann J, Seidenbecher C, Garner CC, Gundelfinger ED . 6 . Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family . Biochemical and Biophysical Research Communications . 264 . 1 . 247–52 . October 1999 . 10527873 . 10.1006/bbrc.1999.1489 .
• Kreienkamp HJ, Zitzer H, Gundelfinger ED, Richter D, Bockers TM . The calcium-independent receptor for alpha-latrotoxin from human and rodent brains interacts with members of the ProSAP/SSTRIP/Shank family of multidomain proteins . The Journal of Biological Chemistry . 275 . 42 . 32387–90 . October 2000 . 10964907 . 10.1074/jbc.C000490200 . free .
• Kreienkamp HJ, Zitzer H, Richter D . Identification of proteins interacting with the rat somatostatin receptor subtype 2 . Journal of Physiology, Paris . 94 . 3–4 . 193–8 . 2001 . 11087996 . 10.1016/S0928-4257(00)00204-7 . 8791865 .
• Okamoto PM, Gamby C, Wells D, Fallon J, Vallee RB . Dynamin isoform-specific interaction with the shank/ProSAP scaffolding proteins of the postsynaptic density and actin cytoskeleton . The Journal of Biological Chemistry . 276 . 51 . 48458–65 . December 2001 . 11583995 . 2715172 . 10.1074/jbc.M104927200 . free .
• Soltau M, Richter D, Kreienkamp HJ . The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42 . Molecular and Cellular Neurosciences . 21 . 4 . 575–83 . December 2002 . 12504591 . 10.1006/mcne.2002.1201 . 572407 .
• Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E . 6 . The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42 . The Journal of Biological Chemistry . 278 . 21 . 19220–9 . May 2003 . 12626503 . 10.1074/jbc.M301052200 . free .
• Han W, Kim KH, Jo MJ, Lee JH, Yang J, Doctor RB, Moe OW, Lee J, Kim E, Lee MG . 6 . Shank2 associates with and regulates Na+/H+ exchanger 3 . The Journal of Biological Chemistry . 281 . 3 . 1461–9 . January 2006 . 16293618 . 10.1074/jbc.M509786200 . free .
• Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y . 6 . Human chromosome 11 DNA sequence and analysis including novel gene identification . Nature . 440 . 7083 . 497–500 . March 2006 . 16554811 . 10.1038/nature04632 . 2006Natur.440..497T . free .

External links

• The SHANK2 Foundation - non-profit supporting families and research into SHANK2 disorders

Notes and References

1. Lim S, Naisbitt S, Yoon J, Hwang JI, Suh PG, Sheng M, Kim E . Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development . The Journal of Biological Chemistry . 274 . 41 . 29510–8 . October 1999 . 10506216 . 10.1074/jbc.274.41.29510 . free .
2. Web site: Entrez Gene: SHANK2 SH3 and multiple ankyrin repeat domains 2.
3. Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED . ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease . Journal of Neurochemistry . 81 . 5 . 903–10 . June 2002 . 12065602 . 10.1046/j.1471-4159.2002.00931.x . 19894590 . free .
4. Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E . 6 . The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42 . The Journal of Biological Chemistry . 278 . 21 . 19220–9 . May 2003 . 12626503 . 10.1074/jbc.M301052200 . free .
5. Du Y, Weed SA, Xiong WC, Marshall TD, Parsons JT . Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons . Molecular and Cellular Biology . 18 . 10 . 5838–51 . October 1998 . 9742101 . 109170 . 10.1128/mcb.18.10.5838 .
6. Naisbitt S, Valtschanoff J, Allison DW, Sala C, Kim E, Craig AM, Weinberg RJ, Sheng M . 6 . Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein . The Journal of Neuroscience . 20 . 12 . 4524–34 . June 2000 . 10844022 . 6772433 . 10.1523/JNEUROSCI.20-12-04524.2000 . free .
7. Boeckers TM, Winter C, Smalla KH, Kreutz MR, Bockmann J, Seidenbecher C, Garner CC, Gundelfinger ED . 6 . Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family . Biochemical and Biophysical Research Communications . 264 . 1 . 247–52 . October 1999 . 10527873 . 10.1006/bbrc.1999.1489 .
8. Okamoto PM, Gamby C, Wells D, Fallon J, Vallee RB . Dynamin isoform-specific interaction with the shank/ProSAP scaffolding proteins of the postsynaptic density and actin cytoskeleton . The Journal of Biological Chemistry . 276 . 51 . 48458–65 . December 2001 . 11583995 . 2715172 . 10.1074/jbc.M104927200 . free .
9. Homann, O. H.. K. Misura . E. Lamas. R. W. Sandrock. P. Nelson. Stefan McDonough. . Whole-Genome Sequencing in Multiplex Families with Psychoses Reveals Mutations in the SHANK2 and SMARCA1 Genes Segregating with Illness . Molecular Psychiatry . 21 . 12 . December 2016 . 1690–95. 10.1038/mp.2016.24 . 27001614 . 5033653 .
10. Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T . 6 . Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments . PLOS Genetics . 10 . 9 . e1004580 . September 2014 . 25188300 . 4154644 . 10.1371/journal.pgen.1004580 . free .
11. Zaslavsky K, Zhang WB, McCready FP, Rodrigues DC, Deneault E, Loo C, Zhao M, Ross PJ, El Hajjar J, Romm A, Thompson T, Piekna A, Wei W, Wang Z, Khattak S, Mufteev M, Pasceri P, Scherer SW, Salter MW, Ellis J . 6 . SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons . Nature Neuroscience . 22 . 4 . 556–564 . April 2019 . 30911184 . 6475597 . 10.1038/s41593-019-0365-8 .
12. Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, Mattheisen M, Wang Y, Coleman JR, Gaspar HA, de Leeuw CA, Steinberg S, Pavlides JM, Trzaskowski M, Byrne EM, Pers TH, Holmans PA, Richards AL, Abbott L, Agerbo E, Akil H, Albani D, Alliey-Rodriguez N, Als TD, Anjorin A, Antilla V, Awasthi S, Badner JA, Bækvad-Hansen M, Barchas JD, Bass N, Bauer M, Belliveau R, Bergen SE, Pedersen CB, Bøen E, Boks MP, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Byerley W, Casas M, Cerrato F, Cervantes P, Chambert K, Charney AW, Chen D, Churchhouse C, Clarke TK, Coryell W, Craig DW, Cruceanu C, Curtis D, Czerski PM, Dale AM, de Jong S, Degenhardt F, Del-Favero J, DePaulo JR, Djurovic S, Dobbyn AL, Dumont A, Elvsåshagen T, Escott-Price V, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Frank J, Fraser C, Freimer NB, Frisén L, Gade K, Gage D, Garnham J, Giambartolomei C, Pedersen MG, Goldstein J, Gordon SD, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Grove J, Guan W, Guzman-Parra J, Hamshere ML, Hautzinger M, Heilbronner U, Herms S, Hipolito M, Hoffmann P, Holland D, Huckins L, Jamain S, Johnson JS, Juréus A, Kandaswamy R, Karlsson R, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Lee PH, Levy SE, Li JZ, Liu C, Lucae S, Maaser A, MacIntyre DJ, Mahon PB, Maier W, Martinsson L, McCarroll S, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Milani L, Montgomery GW, Morris DW, Mühleisen TW, Mullins N, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, O'Donovan C, Loohuis LM, Ori AP, Oruc L, Ösby U, Perlis RH, Perry A, Pfennig A, Potash JB, Purcell SM, Regeer EJ, Reif A, Reinbold CS, Rice JP, Rivas F, Rivera M, Roussos P, Ruderfer DM, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Schork NJ, Shannon Weickert C, Shehktman T, Shilling PD, Sigurdsson E, Slaney C, Smeland OB, Sobell JL, Søholm Hansen C, Spijker AT, St Clair D, Steffens M, Strauss JS, Streit F, Strohmaier J, Szelinger S, Thompson RC, Thorgeirsson TE, Treutlein J, Vedder H, Wang W, Watson SJ, Weickert TW, Witt SH, Xi S, Xu W, Young AH, Zandi P, Zhang P, Zöllner S, Adolfsson R, Agartz I, Alda M, Backlund L, Baune BT, Bellivier F, Berrettini WH, Biernacka JM, Blackwood DH, Boehnke M, Børglum AD, Corvin A, Craddock N, Daly MJ, Dannlowski U, Esko T, Etain B, Frye M, Fullerton JM, Gershon ES, Gill M, Goes F, Grigoroiu-Serbanescu M, Hauser J, Hougaard DM, Hultman CM, Jones I, Jones LA, Kahn RS, Kirov G, Landén M, Leboyer M, Lewis CM, Li QS, Lissowska J, Martin NG, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Metspalu A, Mitchell PB, Morken G, Mors O, Mortensen PB, Müller-Myhsok B, Myers RM, Neale BM, Nimgaonkar V, Nordentoft M, Nöthen MM, O'Donovan MC, Oedegaard KJ, Owen MJ, Paciga SA, Pato C, Pato MT, Posthuma D, Ramos-Quiroga JA, Ribasés M, Rietschel M, Rouleau GA, Schalling M, Schofield PR, Schulze TG, Serretti A, Smoller JW, Stefansson H, Stefansson K, Stordal E, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Werge T, Nurnberger JI, Wray NR, Di Florio A, Edenberg HJ, Cichon S, Ophoff RA, Scott LJ, Andreassen OA, Kelsoe J, Sklar P . 6 . Genome-wide association study identifies 30 loci associated with bipolar disorder . Nature Genetics . 51 . 5 . 793–803 . May 2019 . 31043756 . 6956732 . 10.1038/s41588-019-0397-8 .