Dystroglycan Explained

Dystroglycan is a protein that in humans is encoded by the DAG1 gene.^{[1] [2] [3]}

Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in Homo sapiens on chromosome 3.^[4] There are two exons that are separated by a large intron. The spliced exons code for a protein product that is finally cleaved into two non-covalently associated subunits, [alpha] (N-terminal) and [beta] (C-terminal).

Function

In skeletal muscle the dystroglycan complex works as a transmembrane linkage between the extracellular matrix and the cytoskeleton. [alpha]-dystroglycan is extracellular and binds to merosin [alpha]-2 laminin in the basement membrane, while [beta]-dystroglycan is a transmembrane protein and binds to dystrophin, which is a large rod-like cytoskeletal protein, absent in Duchenne muscular dystrophy patients. Dystrophin binds to intracellular actin cables. In this way, the dystroglycan complex, which links the extracellular matrix to the intracellular actin cables, is thought to provide structural integrity in muscle tissues. The dystroglycan complex is also known to serve as an agrin receptor in muscle, where it may regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. There is also evidence which suggests the function of dystroglycan as a part of the signal transduction pathway because it is shown that Grb2, a mediator of the Ras-related signal pathway, can interact with the cytoplasmic domain of dystroglycan.

Expression

Dystroglycan is widely distributed in non-muscle tissues as well as in muscle tissues. During epithelial morphogenesis of kidney, the dystroglycan complex is shown to act as a receptor for the basement membrane. Dystroglycan expression in Mus musculus brain and neural retina has also been reported. However, the physiological role of dystroglycan in non-muscle tissues remains unclear.

In December 2022, the implications of abnormal dystroglycan expression and/or O-mannosylation on the pathogenesis of cancer have been reviewed.^[5]

Interactions

Dystroglycan has been shown to interact with FYN,^[6] C-src tyrosine kinase,^[6] Src,^[6] NCK1,^[6] Grb2,^[7] Caveolin 3^[8] and SHC1.^[6]

See also

• Dystrophin-associated protein complex
• Actin-binding protein
• Agrin

Further reading

• Matsumura K, Tomé FM, Collin H, Azibi K, Chaouch M, Kaplan JC, Fardeau M, Campbell KP . 6 . Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy . Nature . 359 . 6393 . 320–322 . September 1992 . 1406935 . 10.1038/359320a0 . 4326618 . 1992Natur.359..320M .
• Apel ED, Roberds SL, Campbell KP, Merlie JP . Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex . Neuron . 15 . 1 . 115–126 . July 1995 . 7619516 . 10.1016/0896-6273(95)90069-1 . 589282 . free .
• Yang B, Jung D, Motto D, Meyer J, Koretzky G, Campbell KP . SH3 domain-mediated interaction of dystroglycan and Grb2 . The Journal of Biological Chemistry . 270 . 20 . 11711–11714 . May 1995 . 7744812 . 10.1074/jbc.270.20.11711 . free .
• Yamada H, Shimizu T, Tanaka T, Campbell KP, Matsumura K . Dystroglycan is a binding protein of laminin and merosin in peripheral nerve . FEBS Letters . 352 . 1 . 49–53 . September 1994 . 7925941 . 10.1016/0014-5793(94)00917-1 . 17529055 .
• Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S . Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor . Cell . 77 . 5 . 675–686 . June 1994 . 8205617 . 10.1016/0092-8674(94)90052-3 . 54232250 .
• Ibraghimov-Beskrovnaya O, Milatovich A, Ozcelik T, Yang B, Koepnick K, Francke U, Campbell KP . Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization . Human Molecular Genetics . 2 . 10 . 1651–1657 . October 1993 . 8268918 . 10.1093/hmg/2.10.1651 .
• Yamada H, Denzer AJ, Hori H, Tanaka T, Anderson LV, Fujita S, Fukuta-Ohi H, Shimizu T, Ruegg MA, Matsumura K . 6 . Dystroglycan is a dual receptor for agrin and laminin-2 in Schwann cell membrane . The Journal of Biological Chemistry . 271 . 38 . 23418–23423 . September 1996 . 8798547 . 10.1074/jbc.271.38.23418 . free .
• Tian M, Jacobson C, Gee SH, Campbell KP, Carbonetto S, Jucker M . Dystroglycan in the cerebellum is a laminin alpha 2-chain binding protein at the glial-vascular interface and is expressed in Purkinje cells . The European Journal of Neuroscience . 8 . 12 . 2739–2747 . December 1996 . 8996823 . 10.1111/j.1460-9568.1996.tb01568.x . 1707823 .
• Matsumura K, Chiba A, Yamada H, Fukuta-Ohi H, Fujita S, Endo T, Kobata A, Anderson LV, Kanazawa I, Campbell KP, Shimizu T . 6 . A role of dystroglycan in schwannoma cell adhesion to laminin . The Journal of Biological Chemistry . 272 . 21 . 13904–13910 . May 1997 . 9153251 . 10.1074/jbc.272.21.13904 . free .
• Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM . Identification of novel human WW domain-containing proteins by cloning of ligand targets . The Journal of Biological Chemistry . 272 . 23 . 14611–14616 . June 1997 . 9169421 . 10.1074/jbc.272.23.14611 . free .
• Lorenzo LE, Godin AG, Wang F, St-Louis M, Carbonetto S, Wiseman PW, Ribeiro-da-Silva A, De Koninck Y . 6 . Gephyrin clusters are absent from small diameter primary afferent terminals despite the presence of GABA(A) receptors . The Journal of Neuroscience . 34 . 24 . 8300–8317 . June 2014 . 24920633 . 6608243 . 10.1523/JNEUROSCI.0159-14.2014 .
• Gesemann M, Brancaccio A, Schumacher B, Ruegg MA . Agrin is a high-affinity binding protein of dystroglycan in non-muscle tissue . The Journal of Biological Chemistry . 273 . 1 . 600–605 . January 1998 . 9417121 . 10.1074/jbc.273.1.600 . free .
• Rambukkana A, Yamada H, Zanazzi G, Mathus T, Salzer JL, Yurchenco PD, Campbell KP, Fischetti VA . 6 . Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae . Science . 282 . 5396 . 2076–2079 . December 1998 . 9851927 . 10.1126/science.282.5396.2076 . 1998Sci...282.2076R .
• Cao W, Henry MD, Borrow P, Yamada H, Elder JH, Ravkov EV, Nichol ST, Compans RW, Campbell KP, Oldstone MB . 6 . Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus . Science . 282 . 5396 . 2079–2081 . December 1998 . 9851928 . 10.1126/science.282.5396.2079 . 1998Sci...282.2079C .
• Shimizu H, Hosokawa H, Ninomiya H, Miner JH, Masaki T . Adhesion of cultured bovine aortic endothelial cells to laminin-1 mediated by dystroglycan . The Journal of Biological Chemistry . 274 . 17 . 11995–12000 . April 1999 . 10207021 . 10.1074/jbc.274.17.11995 . free . 2433/180895 . free .
• Côté PD, Moukhles H, Lindenbaum M, Carbonetto S . Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses . Nature Genetics . 23 . 3 . 338–342 . November 1999 . 10610181 . 10.1038/15519 . 564897 .
• Rentschler S, Linn H, Deininger K, Bedford MT, Espanel X, Sudol M . The WW domain of dystrophin requires EF-hands region to interact with beta-dystroglycan . Biological Chemistry . 380 . 4 . 431–442 . April 1999 . 10355629 . 10.1515/BC.1999.057 . 24598356 .
• Tommasi di Vignano A, Di Zenzo G, Sudol M, Cesareni G, Dente L . Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex . FEBS Letters . 471 . 2–3 . 229–234 . April 2000 . 10767429 . 10.1016/S0014-5793(00)01400-9 . 21529759 .
• James M, Nuttall A, Ilsley JL, Ottersbach K, Tinsley JM, Sudol M, Winder SJ . Adhesion-dependent tyrosine phosphorylation of (beta)-dystroglycan regulates its interaction with utrophin . Journal of Cell Science . 113 (Pt 10) . 10 . 1717–1726 . May 2000 . 10769203 . 10.1242/jcs.113.10.1717 . free .
• Russo K, Di Stasio E, Macchia G, Rosa G, Brancaccio A, Petrucci TC . Characterization of the beta-dystroglycan-growth factor receptor 2 (Grb2) interaction . Biochemical and Biophysical Research Communications . 274 . 1 . 93–98 . July 2000 . 10903901 . 10.1006/bbrc.2000.3103 .

External links

• • Overview at sdbonline.org

Notes and References

1. Skynner MJ, Gangadharan U, Coulton GR, Mason RM, Nikitopoulou A, Brown SD, Blanco G . Genetic mapping of the mouse neuromuscular mutation kyphoscoliosis . Genomics . 25 . 1 . 207–213 . January 1995 . 7774920 . 10.1016/0888-7543(95)80127-8 .
2. Ibraghimov-Beskrovnaya O, Ervasti JM, Leveille CJ, Slaughter CA, Sernett SW, Campbell KP . Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix . Nature . 355 . 6362 . 696–702 . February 1992 . 1741056 . 10.1038/355696a0 . 4273337 . 1992Natur.355..696I .
3. Web site: Entrez Gene: DAG1 dystroglycan 1 (dystrophin-associated glycoprotein 1).
4. Spence HJ, Dhillon AS, James M, Winder SJ . Dystroglycan, a scaffold for the ERK-MAP kinase cascade . EMBO Reports . 5 . 5 . 484–489 . May 2004 . 15071496 . 1299052 . 10.1038/sj.embor.7400140 .
5. Quereda C, Pastor À, Martín-Nieto J . Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis . Cancer Cell International . 22 . 1 . 395 . December 2022 . 36494657 . 9733019 . 10.1186/s12935-022-02812-7 . free .
6. Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP . Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins . Biochemistry . 40 . 48 . 14585–14592 . December 2001 . 11724572 . 10.1021/bi011247r .
7. Yang B, Jung D, Motto D, Meyer J, Koretzky G, Campbell KP . SH3 domain-mediated interaction of dystroglycan and Grb2 . The Journal of Biological Chemistry . 270 . 20 . 11711–11714 . May 1995 . 7744812 . 10.1074/jbc.270.20.11711 . free .
8. Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargiacomo M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP . 6 . Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members . The Journal of Biological Chemistry . 275 . 48 . 38048–38058 . December 2000 . 10988290 . 10.1074/jbc.M005321200 . free .