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Gene Review

GJA1  -  gap junction protein, alpha 1, 43kDa

Homo sapiens

Synonyms: AVSD3, CMDR, CX43, Connexin-43, Cx43, ...
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Disease relevance of GJA1

  • We previously showed that Cx26 and Cx43 overexpressed in MDA-MB-231 breast cancer cells inhibited tumor growth in vivo but not in two-dimensional cultures [1].
  • Furthermore, there was heterogeneous Cx43 expression in the carcinoma cells of 14 of the 27 NST carcinomas and the staining was often intercellular and punctate, characteristic of functional connexins [2].
  • Cx43 staining of the myoepithelium was also a feature of the benign lesions and ductal carcinoma in situ (DCIS) [2].
  • Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma [2].
  • Immunoblot analysis showed different CX43 isoforms in control cortex and in low-grade gliomas [3].
  • Based on these data it is concluded that in patients with heart failure, down-regulation of ZO-1 matches the diminished expression levels of connexin 43, suggesting that ZO-1 plays an important role in gap junction formation and gap junction plaque stability [4].

Psychiatry related information on GJA1

  • The distribution of the astrocytic gap junctional protein, connexin43 (Cx43) was compared immunohistochemically with that of amyloid plaques in Alzheimer's Disease (AD) brain [5].

High impact information on GJA1

  • Most of these studies utilized cells in tissue culture that expressed a specific gap junction protein, connexin 43 [6].
  • Phosphorylation of connexin43 (Cx43) on serine368 (S368) has been shown to decrease gap junctional communication via a reduction in unitary channel conductance [7].
  • Our evidence indicates that PKC-dependent phosphorylation of Cx43 at S368 creates dynamic communication compartments that can temporally and spatially regulate wound healing [7].
  • We found that outgrowths of human keratinocytes in wounds or epibole cultures display parallel changes in the expression of laminin 5, integrin alpha3beta1, E-cadherin, and the gap junctional protein connexin 43 [8].
  • When keratinocytes were adhered on laminin 5, both structural (assembly of connexin 43 in gap junctions) and functional (dye transfer) assays showed a two- to threefold increase compared with collagen and five- to eightfold over fibronectin [8].

Chemical compound and disease context of GJA1


Biological context of GJA1


Anatomical context of GJA1

  • OBJECTIVES: To describe a Brazilian family with oculodentodigital dysplasia (ODDD) and to screen for mutations in the gap junction protein alpha 1 (GJA1) gene in this family [18].
  • Furthermore, secreted factors from connexin overexpressing cells inhibited endothelial cell tubulogenesis and migration, and xenografts of Cx43 overexpressing MDA-MB-231 cells showed reduced tumor angiogenesis [1].
  • In the current study, we show that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a three-dimensional environment such that they reduced anchorage-independent cell growth and induced partial redifferentiation of three-dimensional organoids of MDA-MB-231 cells [1].
  • Intercellular calcium waves in HeLa cells expressing GFP-labeled connexin 43, 32, or 26 [19].
  • The aequorin partner of the connexin 43 chimera reported calcium levels in COS-7 cells in at least two different calcium environments [20].

Associations of GJA1 with chemical compounds


Physical interactions of GJA1

  • Here we show that Cx43 binds alpha-tubulin equally well as beta-tubulin [25].
  • In HEK293 cells, by contrast, a connexin-43 mutant lacking the Src phosphorylation site (Tyr265) interacted with ZO-1 despite cotransfection of a constitutively active c-Src [26].
  • Cx43 antiserum could also coprecipitate ZO-1 in the transfected and untransfected ROS cells [27].

Enzymatic interactions of GJA1

  • Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo, but not on S279/S282, which are reported as the consensus phosphorylation sites for MAPK [28].
  • Our results support a model in which activated c-Src phosphorylates the COOH-terminal tail of Cx43 on residue Tyr(265), resulting in a stable interaction between both proteins leading to inhibition of gap junctional communication [29].

Co-localisations of GJA1

  • Because connexin45 (Cx45) has been shown to colocalize with Cx43, we determined whether the number, size, or distribution of Cx45 gap junctions is altered in the failing heart [30].

Regulatory relationships of GJA1


Other interactions of GJA1

  • In summary, Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms, including regulation of EMT and angiogenesis [1].
  • Furthermore, by co-immunoprecipitation, we found that BMK1 directly associates with Cx43 in vivo [28].
  • They constitute separate structures in the Cx32 and Cx43 molecules, the CT domain being an integral part of fast V(j) gating [35].
  • Western blot analysis also demonstrated the presence of Cx40 and Cx43 proteins in T and B lymphocytes in a manner coincidental to the mRNA detection [21].
  • Atrial gap junctions were larger than nodal junctions and contained moderate amounts of Cx40, Cx43, and Cx45 [36].

Analytical, diagnostic and therapeutic context of GJA1


  1. Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis. McLachlan, E., Shao, Q., Wang, H.L., Langlois, S., Laird, D.W. Cancer Res. (2006) [Pubmed]
  2. Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours. Jamieson, S., Going, J.J., D'Arcy, R., George, W.D. J. Pathol. (1998) [Pubmed]
  3. Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Aronica, E., Gorter, J.A., Jansen, G.H., Leenstra, S., Yankaya, B., Troost, D. Acta Neuropathol. (2001) [Pubmed]
  4. Zonula occludens-1 and connexin 43 expression in the failing human heart. Kostin, S. J. Cell. Mol. Med. (2007) [Pubmed]
  5. Elevated connexin43 immunoreactivity at sites of amyloid plaques in Alzheimer's disease. Nagy, J.I., Li, W., Hertzberg, E.L., Marotta, C.A. Brain Res. (1996) [Pubmed]
  6. New roles for astrocytes: gap junction hemichannels have something to communicate. Bennett, M.V., Contreras, J.E., Bukauskas, F.F., Sáez, J.C. Trends Neurosci. (2003) [Pubmed]
  7. Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368. Richards, T.S., Dunn, C.A., Carter, W.G., Usui, M.L., Olerud, J.E., Lampe, P.D. J. Cell Biol. (2004) [Pubmed]
  8. Cellular interaction of integrin alpha3beta1 with laminin 5 promotes gap junctional communication. Lampe, P.D., Nguyen, B.P., Gil, S., Usui, M., Olerud, J., Takada, Y., Carter, W.G. J. Cell Biol. (1998) [Pubmed]
  9. Impaired trafficking of connexins in androgen-independent human prostate cancer cell lines and its mitigation by alpha-catenin. Govindarajan, R., Zhao, S., Song, X.H., Guo, R.J., Wheelock, M., Johnson, K.R., Mehta, P.P. J. Biol. Chem. (2002) [Pubmed]
  10. Increased connexin43 expression in human saphenous veins in culture is associated with intimal hyperplasia. Déglise, S., Martin, D., Probst, H., Saucy, F., Hayoz, D., Waeber, G., Nicod, P., Ris, H.B., Corpataux, J.M., Haefliger, J.A. J. Vasc. Surg. (2005) [Pubmed]
  11. Mutations in the second extracellular region of connexin 43 prevent localization to the plasma membrane, but do not affect its ability to suppress cell growth. Olbina, G., Eckhart, W. Mol. Cancer Res. (2003) [Pubmed]
  12. pp60src-mediated phosphorylation of connexin 43, a gap junction protein. Loo, L.W., Berestecky, J.M., Kanemitsu, M.Y., Lau, A.F. J. Biol. Chem. (1995) [Pubmed]
  13. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Flenniken, A.M., Osborne, L.R., Anderson, N., Ciliberti, N., Fleming, C., Gittens, J.E., Gong, X.Q., Kelsey, L.B., Lounsbury, C., Moreno, L., Nieman, B.J., Peterson, K., Qu, D., Roscoe, W., Shao, Q., Tong, D., Veitch, G.I., Voronina, I., Vukobradovic, I., Wood, G.A., Zhu, Y., Zirngibl, R.A., Aubin, J.E., Bai, D., Bruneau, B.G., Grynpas, M., Henderson, J.E., Henkelman, R.M., McKerlie, C., Sled, J.G., Stanford, W.L., Laird, D.W., Kidder, G.M., Adamson, S.L., Rossant, J. Development (2005) [Pubmed]
  14. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Paznekas, W.A., Boyadjiev, S.A., Shapiro, R.E., Daniels, O., Wollnik, B., Keegan, C.E., Innis, J.W., Dinulos, M.B., Christian, C., Hannibal, M.C., Jabs, E.W. Am. J. Hum. Genet. (2003) [Pubmed]
  15. Human connexin43 gene locus, GJA1, sublocalized to band 6q21-->q23.2. Corcos, I.A., Meese, E.U., Loch-Caruso, R. Cytogenet. Cell Genet. (1993) [Pubmed]
  16. Distribution of genes for gap junction membrane channel proteins on human and mouse chromosomes. Hsieh, C.L., Kumar, N.M., Gilula, N.B., Francke, U. Somat. Cell Mol. Genet. (1991) [Pubmed]
  17. A novel GJA 1 mutation in oculo-dento-digital dysplasia with curly hair and hyperkeratosis. Kelly, S.C., Ratajczak, P., Keller, M., Purcell, S.M., Griffin, T., Richard, G. European journal of dermatology : EJD. (2006) [Pubmed]
  18. A novel mutation in the GJA1 gene in a family with oculodentodigital dysplasia. Vasconcellos, J.P., Melo, M.B., Schimiti, R.B., Bressanim, N.C., Costa, F.F., Costa, V.P. Arch. Ophthalmol. (2005) [Pubmed]
  19. Intercellular calcium waves in HeLa cells expressing GFP-labeled connexin 43, 32, or 26. Paemeleire, K., Martin, P.E., Coleman, S.L., Fogarty, K.E., Carrington, W.A., Leybaert, L., Tuft, R.A., Evans, W.H., Sanderson, M.J. Mol. Biol. Cell (2000) [Pubmed]
  20. Assembly of chimeric connexin-aequorin proteins into functional gap junction channels. Reporting intracellular and plasma membrane calcium environments. Martin, P.E., George, C.H., Castro, C., Kendall, J.M., Capel, J., Campbell, A.K., Revilla, A., Barrio, L.C., Evans, W.H. J. Biol. Chem. (1998) [Pubmed]
  21. Intercellular communication in the immune system: differential expression of connexin40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations. Oviedo-Orta, E., Hoy, T., Evans, W.H. Immunology (2000) [Pubmed]
  22. Connexin43 with a cytoplasmic loop deletion inhibits the function of several connexins. Wang, M., Martínez, A.D., Berthoud, V.M., Seul, K.H., Gemel, J., Valiunas, V., Kumari, S., Brink, P.R., Beyer, E.C. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  23. Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. Dhein, S., Polontchouk, L., Salameh, A., Haefliger, J.A. Biol. Cell (2002) [Pubmed]
  24. Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes. Malone, P., Miao, H., Parker, A., Juarez, S., Hernandez, M.R. Glia (2007) [Pubmed]
  25. Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin. Giepmans, B.N., Verlaan, I., Moolenaar, W.H. Cell Commun. Adhes. (2001) [Pubmed]
  26. c-Src regulates the interaction between connexin-43 and ZO-1 in cardiac myocytes. Toyofuku, T., Akamatsu, Y., Zhang, H., Kuzuya, T., Tada, M., Hori, M. J. Biol. Chem. (2001) [Pubmed]
  27. Connexin45 interacts with zonula occludens-1 and connexin43 in osteoblastic cells. Laing, J.G., Manley-Markowski, R.N., Koval, M., Civitelli, R., Steinberg, T.H. J. Biol. Chem. (2001) [Pubmed]
  28. Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. Cameron, S.J., Malik, S., Akaike, M., Lerner-Marmarosh, N., Yan, C., Lee, J.D., Abe, J., Yang, J. J. Biol. Chem. (2003) [Pubmed]
  29. Interaction of c-Src with gap junction protein connexin-43. Role in the regulation of cell-cell communication. Giepmans, B.N., Hengeveld, T., Postma, F.R., Moolenaar, W.H. J. Biol. Chem. (2001) [Pubmed]
  30. Up-regulation of connexin45 in heart failure. Yamada, K.A., Rogers, J.G., Sundset, R., Steinberg, T.H., Saffitz, J.E. J. Cardiovasc. Electrophysiol. (2003) [Pubmed]
  31. Connexin 43 suppresses human glioblastoma cell growth by down-regulation of monocyte chemotactic protein 1, as discovered using protein array technology. Huang, R., Lin, Y., Wang, C.C., Gano, J., Lin, B., Shi, Q., Boynton, A., Burke, J., Huang, R.P. Cancer Res. (2002) [Pubmed]
  32. Intercellular calcium signaling via gap junction in connexin-43-transfected cells. Toyofuku, T., Yabuki, M., Otsu, K., Kuzuya, T., Hori, M., Tada, M. J. Biol. Chem. (1998) [Pubmed]
  33. Nitric oxide specifically reduces the permeability of Cx37-containing gap junctions to small molecules. Kameritsch, P., Khandoga, N., Nagel, W., Hundhausen, C., Lidington, D., Pohl, U. J. Cell. Physiol. (2005) [Pubmed]
  34. Role of Cx43 phosphorylation and MAP kinase activation in EGF induced enhancement of cell communication in human kidney epithelial cells. Vikhamar, G., Rivedal, E., Mollerup, S., Sanner, T. Cell Adhes. Commun. (1998) [Pubmed]
  35. Molecular dissection of transjunctional voltage dependence in the connexin-32 and connexin-43 junctions. Revilla, A., Castro, C., Barrio, L.C. Biophys. J. (1999) [Pubmed]
  36. Gap junction protein phenotypes of the human heart and conduction system. Davis, L.M., Rodefeld, M.E., Green, K., Beyer, E.C., Saffitz, J.E. J. Cardiovasc. Electrophysiol. (1995) [Pubmed]
  37. SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype. II. Changes in gap junctional intercellular communication. Khoo, N.K., Zhang, Y., Bechberger, J.F., Bond, S.L., Hum, K., Lala, P.K. Int. J. Cancer (1998) [Pubmed]
  38. Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing. Brandner, J.M., Houdek, P., Hüsing, B., Kaiser, C., Moll, I. J. Invest. Dermatol. (2004) [Pubmed]
  39. Gap junction protein connexin 43 serves as a negative marker for a stem cell-containing population of human limbal epithelial cells. Chen, Z., Evans, W.H., Pflugfelder, S.C., Li, D.Q. Stem Cells (2006) [Pubmed]
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