Wikipedia

Integrin alpha 7

(Redirected from ITGA7)

Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene.[5][6] 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.

ITGA7
Identifiers
AliasesITGA7, integrin subunit alpha 7
External IDsOMIM: 600536; MGI: 102700; HomoloGene: 37592; GeneCards: ITGA7; OMA:ITGA7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3679

16404

Ensembl

ENSG00000135424

ENSMUSG00000025348

UniProt

Q13683

Q61738

RefSeq (mRNA)

NM_008398
NM_001330160

RefSeq (protein)

n/a

Location (UCSC)Chr 12: 55.68 – 55.72 MbChr 10: 128.77 – 128.79 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

edit

ITGA7 encodes the protein alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181 amino acids in length.[7] 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).[8] 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[9] and are developmentally regulated in mouse and rat muscle tissue.[9][10][11][12][13] 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.[9] 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.[6][14] 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.[15]

Alpha-7 integrin is highly expressed in striated muscle, namely skeletal and cardiac muscle, and functions as the major laminin-binding integrin.[16] It was later shown that alpha-7 integrin is also highly expressed in smooth muscle.[17] 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.[18]

Function

edit

The function of alpha-7 integrin, as is the case for most integrins is to mediate cell membrane interactions with extracellular matrix.[19]

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.[20] 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.[21] In human skeletal muscle, alpha-7 integrin is also developmentally regulated, being first detected at age 2.[8]

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.[10][22][23] It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in skeletal muscle cells;[24] 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.[25] 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.[26] 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.[27] 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.[28]

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.[29]

Clinical Significance

edit

Mutations in ITGA7 have been found in patients with unclassified congenital myopathy.[30] 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.[31]

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.[8]

Interactions

edit

ITGA7 has been shown to interact with:

See also

edit

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135424 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025348 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Wang W, Wu W, Desai T, Ward DC, Kaufman SJ (Aug 1995). "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. doi:10.1016/0888-7543(95)80176-M. PMID 7607681.
  6. ^ a b "Entrez Gene: ITGA7 integrin, alpha 7".
  7. ^ "Protein sequence of human ITGA7 (Uniprot ID: Q13683)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 24 September 2015. Retrieved 20 July 2015.
  8. ^ a b c Cohn RD, Mayer U, Saher G, Herrmann R, van der Flier A, Sonnenberg A, Sorokin L, Voit T (March 1999). "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. doi:10.1016/s0022-510x(99)00012-x. PMID 10371075. S2CID 53300469.
  9. ^ a b c Ziober BL, Vu MP, Waleh N, Crawford J, Lin CS, Kramer RH (December 1993). "Alternative extracellular and cytoplasmic domains of the integrin alpha 7 subunit are differentially expressed during development". J. Biol. Chem. 268 (35): 26773–83. doi:10.1016/S0021-9258(19)74380-4. PMID 8253814.
  10. ^ a b Maitra N, Flink IL, Bahl JJ, Morkin E (September 2000). "Expression of alpha and beta integrins during terminal differentiation of cardiomyocytes". Cardiovasc. Res. 47 (4): 715–25. doi:10.1016/s0008-6363(00)00140-1. PMID 10974220.
  11. ^ Collo G, Starr L, Quaranta V (September 1993). "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. doi:10.1016/S0021-9258(17)46729-9. PMID 8360188.
  12. ^ Song WK, Wang W, Sato H, Bielser DA, Kaufman SJ (December 1993). "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) (4): 1139–52. doi:10.1242/jcs.106.4.1139. PMID 8126096.
  13. ^ Ziober BL, Kramer RH (September 1996). "Identification and characterization of the cell type-specific and developmentally regulated alpha7 integrin gene promoter". J. Biol. Chem. 271 (37): 22915–22. doi:10.1074/jbc.271.37.22915. PMID 8798472.
  14. ^ Leung, E; Lim, SP; Berg, R; Yang, Y; Ni, J; Wang, SX; Krissansen, GW (4 February 1998). "A novel extracellular domain variant of the human integrin alpha 7 subunit generated by alternative intron splicing". Biochemical and Biophysical Research Communications. 243 (1): 317–25. doi:10.1006/bbrc.1998.8092. PMID 9473524.
  15. ^ Vignier N, Moghadaszadeh B, Gary F, Beckmann J, Mayer U, Guicheney P (July 1999). "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. doi:10.1006/bbrc.1999.0916. PMID 10403775.
  16. ^ Kaufman SJ, Foster RF, Haye KR, Faiman LE (June 1985). "Expression of a developmentally regulated antigen on the surface of skeletal and cardiac muscle cells". J. Cell Biol. 100 (6): 1977–87. doi:10.1083/jcb.100.6.1977. PMC 2113591. PMID 3889014.
  17. ^ Yao CC, Breuss J, Pytela R, Kramer RH (July 1997). "Functional expression of the alpha 7 integrin receptor in differentiated smooth muscle cells". J. Cell Sci. 110 ( Pt 13) (13): 1477–87. doi:10.1242/jcs.110.13.1477. PMID 9224765.
  18. ^ Velling T, Collo G, Sorokin L, Durbeej M, Zhang H, Gullberg D (December 1996). "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. doi:10.1002/(SICI)1097-0177(199612)207:4<355::AID-AJA1>3.0.CO;2-G. PMID 8950511.
  19. ^ Hynes RO (April 1992). "Integrins: versatility, modulation, and signaling in cell adhesion". Cell. 69 (1): 11–25. doi:10.1016/0092-8674(92)90115-s. PMID 1555235. S2CID 32774108.
  20. ^ Yao CC, Ziober BL, Sutherland AE, Mendrick DL, Kramer RH (December 1996). "Laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrin receptor". J. Cell Sci. 109 ( Pt 13) (13): 3139–50. doi:10.1242/jcs.109.13.3139. PMID 9004048.
  21. ^ Brancaccio M, Cabodi S, Belkin AM, Collo G, Koteliansky VE, Tomatis D, Altruda F, Silengo L, Tarone G (March 1998). "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. doi:10.3109/15419069809040291. PMID 9686317.
  22. ^ a b c Samson T, Smyth N, Janetzky S, Wendler O, Müller JM, Schüle R, von der Mark H, von der Mark K, Wixler V (Jul 2004). "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. doi:10.1074/jbc.M312894200. PMID 15117962.
  23. ^ Galie PA, Khalid N, Carnahan KE, Westfall MV, Stegemann JP (2013). "Substrate stiffness affects sarcomere and costamere structure and electrophysiological function of isolated adult cardiomyocytes". Cardiovasc. Pathol. 22 (3): 219–27. doi:10.1016/j.carpath.2012.10.003. PMC 3610795. PMID 23266222.
  24. ^ Zolkiewska A, Moss J (1997). "The α7 Integrin as a Target Protein for Cell Surface Mono-ADP-Ribosylation in Muscle Cells". ADP-Ribosylation in Animal Tissues. Advances in Experimental Medicine and Biology. Vol. 419. pp. 297–303. doi:10.1007/978-1-4419-8632-0_39. ISBN 978-1-4613-4652-4. PMID 9193669.
  25. ^ Mayer U, Saher G, Fässler R, Bornemann A, Echtermeyer F, von der Mark H, Miosge N, Pöschl E, von der Mark K (November 1997). "Absence of integrin alpha 7 causes a novel form of muscular dystrophy". Nat. Genet. 17 (3): 318–23. doi:10.1038/ng1197-318. PMID 9354797. S2CID 23724091.
  26. ^ Allikian, MJ; Hack, AA; Mewborn, S; Mayer, U; McNally, EM (1 August 2004). "Genetic compensation for sarcoglycan loss by integrin alpha7beta1 in muscle". Journal of Cell Science. 117 (Pt 17): 3821–30. doi:10.1242/jcs.01234. PMID 15252120. S2CID 86082596.
  27. ^ Guo C, Willem M, Werner A, Raivich G, Emerson M, Neyses L, Mayer U (March 2006). "Absence of alpha 7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy". Hum. Mol. Genet. 15 (6): 989–98. doi:10.1093/hmg/ddl018. PMID 16476707.
  28. ^ Heller KN, Montgomery CL, Janssen PM, Clark KR, Mendell JR, Rodino-Klapac LR (March 2013). "AAV-mediated overexpression of human α7 integrin leads to histological and functional improvement in dystrophic mice". Mol. Ther. 21 (3): 520–5. doi:10.1038/mt.2012.281. PMC 3589167. PMID 23319059.
  29. ^ Mielenz D, Hapke S, Pöschl E, von Der Mark H, von Der Mark K (April 2001). "The integrin alpha 7 cytoplasmic domain regulates cell migration, lamellipodia formation, and p130CAS/Crk coupling". J. Biol. Chem. 276 (16): 13417–26. doi:10.1074/jbc.M011481200. PMID 11278916.
  30. ^ Hayashi YK, Chou FL, Engvall E, Ogawa M, Matsuda C, Hirabayashi S, et al. (May 1998). "Mutations in the integrin alpha7 gene cause congenital myopathy". Nat. Genet. 19 (1): 94–7. doi:10.1038/ng0598-94. PMID 9590299. S2CID 40229216.
  31. ^ Esposito T, Sampaolo S, Limongelli G, Varone A, Formicola D, Diodato D, et al. (June 2013). "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. doi:10.1186/1750-1172-8-91. PMC 3695851. PMID 23800289.
  32. ^ a b Vachon PH, Xu H, Liu L, Loechel F, Hayashi Y, Arahata K, Reed JC, Wewer UM, Engvall E (October 1997). "Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy". J. Clin. Invest. 100 (7): 1870–81. doi:10.1172/JCI119716. PMC 508374. PMID 9312189.
  33. ^ Hodges BL, Hayashi YK, Nonaka I, Wang W, Arahata K, Kaufman SJ (November 1997). "Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies". J. Cell Sci. 110 ( Pt 22) (22): 2873–81. doi:10.1242/jcs.110.22.2873. PMID 9427295.

Further reading

edit
edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Integrin_alpha_7&oldid=1212904323"