Integrin alpha 7 explained

Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene.[1] [2] Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.

Structure

ITGA7 encodes the protein alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181 amino acids in length.[3] Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha-7 integrin undergoes post-translational cleavage within the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that binds to the extracellular matrix protein laminin-1. The primary binding partners of alpha-7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1).[4] Alpha-7/beta-1 is the major integrin complex expressed in differentiated muscle cells.

Splice variants of alpha-7 integrin that differ in both the extracellular and cytoplasmic domains exist in the mouse[5] and are developmentally regulated in mouse and rat muscle tissue.[5] [6] [7] [8] [9] The X1/X2 alternative splicing region lies in the extracellular domain and alters the ligand binding site; specifically, the conserved homology repeat domains 3 and 4.[5] The first identified human transcript contains extracellular and cytoplasmic domains corresponding to the mouse X2 and B variants, respectively. A unique extracellular splice variant was also identified in human.[10] The differentially spliced variants detected in rodents have also been detected in humans. Major cytoplasmic, developmentally regulated variants, alpha-7A and alpha-7B, as well as extracellular variants, X1 and X2 were identified in humans. Moreover, the D variant, but not the C variant was detected in humans.[11]

Alpha-7 integrin is highly expressed in striated muscle, namely skeletal and cardiac muscle, and functions as the major laminin-binding integrin.[12] It was later shown that alpha-7 integrin is also highly expressed in smooth muscle.[13] The two major splice variants of alpha-7 integrin appear to have developmentally regulated expression; alpha-7A integrin is expressed solely in skeletal muscle, however alpha-7B integrin is expressed more loosely in striated muscle as well as the vasculature.[14]

Function

The function of alpha-7 integrin, as is the case for most integrins is to mediate cell membrane interactions with extracellular matrix.[15]

The alpha-7/beta-1 integrin complex clearly plays a role in the development of striated muscle and smooth muscle. Alpha-7/beta-1 integrin promotes the adhesion and motility of myoblasts, and is likely important in the recruitment of myogenic precursors during muscle differentiation.[16] It was shown however that beta-1D integrin appears at embryonic day 11 and alpha-7 integrin does not appear until embryonic day 17; thus, beta-1D associates with alternate alpha subunits (alpha-5, alpha-6A) prior to alpha-7.[17] In human skeletal muscle, alpha-7 integrin is also developmentally regulated, being first detected at age 2.[4]

In adult striated muscle cells, alpha-7 integrin (complexed to beta-1 integrin) is localized to Z-discs and costamere structures, bound to the four and one half LIM domain proteins, FHL1 and FHL2.[6] [18] It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in skeletal muscle cells;[19] however, the functional significance of this modification has not been investigated.

Insights into the function of alpha-7 integrin have come from studies employing mouse transgenesis. A mouse expressing a null allele of the ITGA7 gene are viable, suggesting that alpha-7 integrin is not essential for normal myogenesis; however, these mice develop a phenotype that resembles muscular dystrophy. In soleus muscle, there was a significant disruption of myotendinous junctions, variation in the size of fibers, centrally located nuclei, necrosis, phagocytosis, and elevated serum levels of creatine kinase.[20] It has also been proposed that alpha-7 integrin and gamma-sarcoglycan have overlapping functions in skeletal muscle. In support of this, a double knockout of gamma-sarcoglycan and alpha-7 integrin produced a phenotype that was far worse than either knockout alone. Mice died within 1 month of birth and had severe muscle degeneration, suggesting that the roles of these proteins may overlap to maintain the stability of the sarcolemma.[21] Moreover, the double knockout of dystrophin and alpha-7 integrin produced a Duchenne muscular dystrophy-like phenotype, and demonstrated that alterations in alpha-7 integrin affect the pathological changes observed in dystrophin deficiencies.[22] In support of this notion, AAV overexpression of ITGA7 in skeletal muscle of Duchenne muscular dystrophy (DMD) mice showed a significant protective effect against adverse functional parameters associated with DMD, combined with a reversal of these negative features, suggesting that alpha-7 integrin may be a potential therapeutic candidate to treat Duchenne muscular dystrophy.[23]

Studies employing mutant alpha-7 integrin constructs have shown that the cytoplasmic tail of alpha-7B integrin is essential for regulation of lamellipodia formation and regulation of cell mobility regulation via laminin-1/E8 and p130(CAS)/Crk complex formation.[24]

Clinical Significance

Mutations in ITGA7 have been found in patients with unclassified congenital myopathy.[25] Additionally, in patients with severe congenital fiber type disproportion and left ventricular non-compaction cardiomyopathy, a missense mutation, Glu882Lys, was identified in ITGA7 along with a missense mutation in MYH7B, both novel disease genes having a synergistic effect on disease severity.[26]

Alpha-7B integrin expression has been shown to be significantly decreased at sarcolemmal membranes in patients with laminin alpha2 chain-deficient congenital muscular dystrophy. Additionally, in Duchenne muscular dystrophy and Becker muscular dystrophy, the expression of alpha-7B integrin was enhanced.[4]

Interactions

ITGA7 has been shown to interact with:

See also

Further reading

External links

Notes and References

  1. Wang W, Wu W, Desai T, Ward DC, Kaufman SJ . Localization of the alpha 7 integrin gene (ITGA7) on human chromosome 12q13: clustering of integrin and Hox genes implies parallel evolution of these gene families . Genomics . 26 . 3 . 568–70 . Aug 1995 . 7607681 . 10.1016/0888-7543(95)80176-M . free .
  2. Web site: Entrez Gene: ITGA7 integrin, alpha 7.
  3. Web site: Protein sequence of human ITGA7 (Uniprot ID: Q13683). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 20 July 2015. 24 September 2015. https://web.archive.org/web/20150924025545/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q13683. dead.
  4. Cohn RD, Mayer U, Saher G, Herrmann R, van der Flier A, Sonnenberg A, Sorokin L, Voit T . Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle . J. Neurol. Sci. . 163 . 2 . 140–52 . March 1999 . 10371075 . 10.1016/s0022-510x(99)00012-x. 53300469 .
  5. Ziober BL, Vu MP, Waleh N, Crawford J, Lin CS, Kramer RH . Alternative extracellular and cytoplasmic domains of the integrin alpha 7 subunit are differentially expressed during development . J. Biol. Chem. . 268 . 35 . 26773–83 . December 1993 . 10.1016/S0021-9258(19)74380-4 . 8253814 . free .
  6. Maitra N, Flink IL, Bahl JJ, Morkin E . Expression of alpha and beta integrins during terminal differentiation of cardiomyocytes . Cardiovasc. Res. . 47 . 4 . 715–25 . September 2000 . 10974220 . 10.1016/s0008-6363(00)00140-1. free .
  7. Collo G, Starr L, Quaranta V . A new isoform of the laminin receptor integrin alpha 7 beta 1 is developmentally regulated in skeletal muscle . J. Biol. Chem. . 268 . 25 . 19019–24 . September 1993 . 10.1016/S0021-9258(17)46729-9 . 8360188 . free .
  8. Song WK, Wang W, Sato H, Bielser DA, Kaufman SJ . Expression of alpha 7 integrin cytoplasmic domains during skeletal muscle development: alternate forms, conformational change, and homologies with serine/threonine kinases and tyrosine phosphatases . J. Cell Sci. . 106 (Pt 4) . 1139–52 . December 1993 . 4 . 10.1242/jcs.106.4.1139 . 8126096.
  9. Ziober BL, Kramer RH . Identification and characterization of the cell type-specific and developmentally regulated alpha7 integrin gene promoter . J. Biol. Chem. . 271 . 37 . 22915–22 . September 1996 . 8798472 . 10.1074/jbc.271.37.22915 . free .
  10. Leung. E. Lim. SP. Berg. R. Yang. Y. Ni. J. Wang. SX. Krissansen. GW. A novel extracellular domain variant of the human integrin alpha 7 subunit generated by alternative intron splicing.. Biochemical and Biophysical Research Communications. 4 February 1998. 243. 1. 317–25. 9473524. 10.1006/bbrc.1998.8092.
  11. Vignier N, Moghadaszadeh B, Gary F, Beckmann J, Mayer U, Guicheney P . Structure, genetic localization, and identification of the cardiac and skeletal muscle transcripts of the human integrin alpha7 gene (ITGA7) . Biochem. Biophys. Res. Commun. . 260 . 2 . 357–64 . July 1999 . 10403775 . 10.1006/bbrc.1999.0916 .
  12. Kaufman SJ, Foster RF, Haye KR, Faiman LE . Expression of a developmentally regulated antigen on the surface of skeletal and cardiac muscle cells . J. Cell Biol. . 100 . 6 . 1977–87 . June 1985 . 3889014 . 2113591 . 10.1083/jcb.100.6.1977.
  13. Yao CC, Breuss J, Pytela R, Kramer RH . Functional expression of the alpha 7 integrin receptor in differentiated smooth muscle cells . J. Cell Sci. . 110 (Pt 13) . 1477–87 . July 1997 . 13 . 10.1242/jcs.110.13.1477 . 9224765 .
  14. Velling T, Collo G, Sorokin L, Durbeej M, Zhang H, Gullberg D . Distinct alpha 7A beta 1 and alpha 7B beta 1 integrin expression patterns during mouse development: alpha 7A is restricted to skeletal muscle but alpha 7B is expressed in striated muscle, vasculature, and nervous system . Dev. Dyn. . 207 . 4 . 355–71 . December 1996 . 8950511 . 10.1002/(SICI)1097-0177(199612)207:4<355::AID-AJA1>3.0.CO;2-G . free .
  15. Hynes RO . Integrins: versatility, modulation, and signaling in cell adhesion . Cell . 69 . 1 . 11–25 . April 1992 . 1555235 . 10.1016/0092-8674(92)90115-s. 32774108 .
  16. Yao CC, Ziober BL, Sutherland AE, Mendrick DL, Kramer RH . Laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrin receptor . J. Cell Sci. . 109 (Pt 13) . 3139–50 . December 1996 . 13 . 10.1242/jcs.109.13.3139 . 9004048 .
  17. Brancaccio M, Cabodi S, Belkin AM, Collo G, Koteliansky VE, Tomatis D, Altruda F, Silengo L, Tarone G . Differential onset of expression of alpha 7 and beta 1D integrins during mouse heart and skeletal muscle development . Cell Adhes. Commun. . 5 . 3 . 193–205 . March 1998 . 9686317 . 10.3109/15419069809040291. free .
  18. Galie PA, Khalid N, Carnahan KE, Westfall MV, Stegemann JP . Substrate stiffness affects sarcomere and costamere structure and electrophysiological function of isolated adult cardiomyocytes . Cardiovasc. Pathol. . 22 . 3 . 219–27 . 2013 . 23266222 . 3610795 . 10.1016/j.carpath.2012.10.003 .
  19. Book: Zolkiewska A, Moss J . The α7 Integrin as a Target Protein for Cell Surface Mono-ADP-Ribosylation in Muscle Cells . ADP-Ribosylation in Animal Tissues . 419 . 297–303 . 1997 . 9193669 . 10.1007/978-1-4419-8632-0_39. Advances in Experimental Medicine and Biology . 978-1-4613-4652-4 .
  20. Mayer U, Saher G, Fässler R, Bornemann A, Echtermeyer F, von der Mark H, Miosge N, Pöschl E, von der Mark K . Absence of integrin alpha 7 causes a novel form of muscular dystrophy . Nat. Genet. . 17 . 3 . 318–23 . November 1997 . 9354797 . 10.1038/ng1197-318 . 23724091 .
  21. Allikian. MJ. Hack. AA. Mewborn. S. Mayer. U. McNally. EM. Genetic compensation for sarcoglycan loss by integrin alpha7beta1 in muscle.. Journal of Cell Science. 1 August 2004. 117. Pt 17. 3821–30. 15252120. 10.1242/jcs.01234. 86082596 .
  22. Guo C, Willem M, Werner A, Raivich G, Emerson M, Neyses L, Mayer U . Absence of alpha 7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy . Hum. Mol. Genet. . 15 . 6 . 989–98 . March 2006 . 16476707 . 10.1093/hmg/ddl018 . free .
  23. Heller KN, Montgomery CL, Janssen PM, Clark KR, Mendell JR, Rodino-Klapac LR . AAV-mediated overexpression of human α7 integrin leads to histological and functional improvement in dystrophic mice . Mol. Ther. . 21 . 3 . 520–5 . March 2013 . 23319059 . 3589167 . 10.1038/mt.2012.281 .
  24. Mielenz D, Hapke S, Pöschl E, von Der Mark H, von Der Mark K . The integrin alpha 7 cytoplasmic domain regulates cell migration, lamellipodia formation, and p130CAS/Crk coupling . J. Biol. Chem. . 276 . 16 . 13417–26 . April 2001 . 11278916 . 10.1074/jbc.M011481200 . free .
  25. Hayashi YK, Chou FL, Engvall E, Ogawa M, Matsuda C, Hirabayashi S, Yokochi K, Ziober BL, Kramer RH, Kaufman SJ, Ozawa E, Goto Y, Nonaka I, Tsukahara T, Wang JZ, Hoffman EP, Arahata K. 6 . Mutations in the integrin alpha7 gene cause congenital myopathy . Nat. Genet. . 19 . 1 . 94–7 . May 1998 . 9590299 . 10.1038/ng0598-94 . 40229216 .
  26. Esposito T, Sampaolo S, Limongelli G, Varone A, Formicola D, Diodato D, Farina O, Napolitano F, Pacileo G, Gianfrancesco F, Di Iorio G. 6 . Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy . Orphanet J Rare Dis . 8 . 91 . June 2013 . 23800289 . 3695851 . 10.1186/1750-1172-8-91 . free .
  27. Vachon PH, Xu H, Liu L, Loechel F, Hayashi Y, Arahata K, Reed JC, Wewer UM, Engvall E . Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy . J. Clin. Invest. . 100 . 7 . 1870–81 . October 1997 . 9312189 . 508374 . 10.1172/JCI119716 .
  28. Hodges BL, Hayashi YK, Nonaka I, Wang W, Arahata K, Kaufman SJ . Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies . J. Cell Sci. . 110 (Pt 22) . 2873–81 . November 1997 . 22 . 10.1242/jcs.110.22.2873 . 9427295 .
  29. Samson T, Smyth N, Janetzky S, Wendler O, Müller JM, Schüle R, von der Mark H, von der Mark K, Wixler V . The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor . J. Biol. Chem. . 279 . 27 . 28641–52 . Jul 2004 . 15117962 . 10.1074/jbc.M312894200 . free .

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