Gap junction trafficking and regulation (Homo sapiens)

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1. Bruzzone R.; ''Learning the language of cell-cell communication through connexin channels.''; PubMed Europe PMC Scholia
2. Martin PE, Mambetisaeva ET, Archer DA, George CH, Evans WH.; ''Analysis of gap junction assembly using mutated connexins detected in Charcot-Marie-Tooth X-linked disease.''; PubMed Europe PMC Scholia
3. Huang S, Dudez T, Scerri I, Thomas MA, Giepmans BN, Suter S, Chanson M.; ''Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation.''; PubMed Europe PMC Scholia
4. Segretain D, Falk MM.; ''Regulation of connexin biosynthesis, assembly, gap junction formation, and removal.''; PubMed Europe PMC Scholia
5. Giepmans BN, Hengeveld T, Postma FR, Moolenaar WH.; ''Interaction of c-Src with gap junction protein connexin-43. Role in the regulation of cell-cell communication.''; PubMed Europe PMC Scholia
6. Martin PE, Blundell G, Ahmad S, Errington RJ, Evans WH.; ''Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels.''; PubMed Europe PMC Scholia
7. Spinella F, Rosanò L, Di Castro V, Nicotra MR, Natali PG, Bagnato A.; ''Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells.''; PubMed Europe PMC Scholia
8. Kelsell DP, Dunlop J, Hodgins MB.; ''Human diseases: clues to cracking the connexin code?''; PubMed Europe PMC Scholia
9. Ahmad S, Diez JA, George CH, Evans WH.; ''Synthesis and assembly of connexins in vitro into homomeric and heteromeric functional gap junction hemichannels.''; PubMed Europe PMC Scholia
10. Falk MM, Buehler LK, Kumar NM, Gilula NB.; ''Cell-free synthesis and assembly of connexins into functional gap junction membrane channels.''; PubMed Europe PMC Scholia
11. Falk MM, Kumar NM, Gilula NB.; ''Membrane insertion of gap junction connexins: polytopic channel forming membrane proteins.''; PubMed Europe PMC Scholia
12. Piehl M, Lehmann C, Gumpert A, Denizot JP, Segretain D, Falk MM.; ''Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process.''; PubMed Europe PMC Scholia
13. Wang M, Berthoud VM, Beyer EC.; ''Connexin43 increases the sensitivity of prostate cancer cells to TNFalpha-induced apoptosis.''; PubMed Europe PMC Scholia
14. Simon AM, Goodenough DA.; ''Diverse functions of vertebrate gap junctions.''; PubMed Europe PMC Scholia
15. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM.; ''Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells.''; PubMed Europe PMC Scholia
16. Fishman GI, Moreno AP, Spray DC, Leinwand LA.; ''Functional analysis of human cardiac gap junction channel mutants.''; PubMed Europe PMC Scholia
17. Wong RC, Pébay A, Nguyen LT, Koh KL, Pera MF.; ''Presence of functional gap junctions in human embryonic stem cells.''; PubMed Europe PMC Scholia

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DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
AP2M1 [lysosomal membrane]	Protein	Q96CW1 (Uniprot-TrEMBL)
AP2M1 [plasma membrane]	Protein	Q96CW1 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Connexin 26 Connexon	Complex	REACT_21620 (Reactome)
Connexin 26:Connexin 32 connexon	Complex	REACT_9762 (Reactome)
Connexin 32 connexon	Complex	REACT_9765 (Reactome)
Connexin 43 hemi-channel	Complex	REACT_10289 (Reactome)
Connexin 43 connexon in Golgi transport vesicle	Complex	REACT_10502 (Reactome)
Connexin 43 connexon	Complex	REACT_9901 (Reactome)
Connexon 26	Complex	REACT_10376 (Reactome)
Cx26/Cx32	Protein	REACT_9641 (Reactome)
Cx26/Cx32	Protein	REACT_9706 (Reactome)
Cx43 :ZO-1 gap junction	Complex	REACT_10329 (Reactome)
Cx43:TJP1	Complex	REACT_10187 (Reactome)
Cx43:ZO-1:c-src gap junction	Complex	REACT_10511 (Reactome)
DAB2 [lysosomal membrane]	Protein	P98082 (Uniprot-TrEMBL)
DAB2 [plasma membrane]	Protein	P98082 (Uniprot-TrEMBL)
DAB2	Protein	P98082 (Uniprot-TrEMBL)
Docked Cx43-containing transport vesicles	Complex	REACT_10422 (Reactome)
Dynamin	Protein	REACT_10614 (Reactome)
GJA1 [Golgi-associated vesicle membrane]	Protein	P17302 (Uniprot-TrEMBL)
GJA1 [Golgi membrane]	Protein	P17302 (Uniprot-TrEMBL)
GJA1 [plasma membrane]	Protein	P17302 (Uniprot-TrEMBL)
GJA1	Protein	P17302 (Uniprot-TrEMBL)
GJB1 [endoplasmic reticulum membrane]	Protein	P08034 (Uniprot-TrEMBL)
GJB1 [endoplasmic reticulum-Golgi intermediate compartment]	Protein	P08034 (Uniprot-TrEMBL)
GJB1	Protein	P08034 (Uniprot-TrEMBL)
GJB2 [endoplasmic reticulum-Golgi intermediate compartment]	Protein	P29033 (Uniprot-TrEMBL)
GJB2 [plasma membrane]	Protein	P29033 (Uniprot-TrEMBL)
GJB2	Protein	P29033 (Uniprot-TrEMBL)
Hemi-channels	Complex	REACT_10652 (Reactome)
Invaginating gap junction plaques	Complex	REACT_10333 (Reactome)
Junctional channel	Complex	REACT_10244 (Reactome)
MYO6 [lysosomal membrane]	Protein	Q9UM54 (Uniprot-TrEMBL)
MYO6	Protein	Q9UM54 (Uniprot-TrEMBL)
Monomeric connexin protein	Protein	REACT_9675 (Reactome)
Planar gap junction plaques associated with Dab2 and Dynamin	Complex	REACT_10413 (Reactome)
SRC-2 [plasma membrane]	Protein	P12931-2 (Uniprot-TrEMBL)
SRC-2	Protein	P12931-2 (Uniprot-TrEMBL)
TJP1 [Golgi-associated vesicle membrane]	Protein	Q07157 (Uniprot-TrEMBL)
TJP1 [plasma membrane]	Protein	Q07157 (Uniprot-TrEMBL)
TJP1	Protein	Q07157 (Uniprot-TrEMBL)
c-src-associated Cx43 junctional channel	Complex	REACT_10199 (Reactome)
closed Cx43 junctional channel	Complex	REACT_10597 (Reactome)
connexons in Golgi transport vesicle docked to microtubules	Complex	REACT_10450 (Reactome)
gap junction plaque	Complex	REACT_10558 (Reactome)
microtubule		REACT_10446 (Reactome)
p-Y265-GJA1 [plasma membrane]	Protein	P17302 (Uniprot-TrEMBL)
phospho-Y265 Cx43:ZO-1 gap junction	Complex	REACT_10386 (Reactome)
planar gap junction plaques associated with Dab2	Complex	REACT_10755 (Reactome)
planar gap junction plaques	Complex	REACT_10866 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_9997 (Reactome)
ATP			REACT_9997 (Reactome)
Connexin 26 Connexon			REACT_21353 (Reactome)
	Connexin 26:Connexin 32 connexon	Arrow	REACT_9520 (Reactome)
	Connexin 32 connexon	Arrow	REACT_9494 (Reactome)
	Connexin 43 hemi-channel	Arrow	REACT_10004 (Reactome)
	Connexin 43 connexon in Golgi transport vesicle	Arrow	REACT_10110 (Reactome)
Connexin 43 connexon in Golgi transport vesicle			REACT_10011 (Reactome)
Connexin 43 connexon in Golgi transport vesicle			REACT_10060 (Reactome)
	Connexin 43 connexon	Arrow	REACT_9415 (Reactome)
Connexin 43 connexon			REACT_10110 (Reactome)
	Connexon 26	Arrow	REACT_21353 (Reactome)
	Cx26/Cx32	Arrow	REACT_9503 (Reactome)
Cx26/Cx32			REACT_9503 (Reactome)
Cx43 :ZO-1 gap junction			REACT_9975 (Reactome)
	Cx43:TJP1	Arrow	REACT_10060 (Reactome)
	Cx43:ZO-1:c-src gap junction	Arrow	REACT_9975 (Reactome)
Cx43:ZO-1:c-src gap junction			REACT_9997 (Reactome)
Cx43:ZO-1:c-src gap junction		mim-catalysis	REACT_9997 (Reactome)
DAB2			REACT_9951 (Reactome)
	Docked Cx43-containing transport vesicles	Arrow	REACT_10108 (Reactome)
Docked Cx43-containing transport vesicles			REACT_10004 (Reactome)
Dynamin			REACT_9969 (Reactome)
	GJA1	Arrow	REACT_9473 (Reactome)
	GJA1	Arrow	REACT_9499 (Reactome)
GJA1			REACT_9415 (Reactome)
GJA1			REACT_9499 (Reactome)
	GJB1	Arrow	REACT_9442 (Reactome)
GJB1			REACT_9494 (Reactome)
GJB1			REACT_9520 (Reactome)
GJB1		mim-catalysis	REACT_9494 (Reactome)
	GJB2	Arrow	REACT_115750 (Reactome)
GJB2			REACT_9520 (Reactome)
Hemi-channels			REACT_9990 (Reactome)
	Invaginating gap junction plaques	Arrow	REACT_9971 (Reactome)
Invaginating gap junction plaques			REACT_10083 (Reactome)
	Junctional channel	Arrow	REACT_9990 (Reactome)
Junctional channel			REACT_10046 (Reactome)
MYO6			REACT_9971 (Reactome)
	Monomeric connexin protein	Arrow	REACT_9410 (Reactome)
	Planar gap junction plaques associated with Dab2 and Dynamin	Arrow	REACT_9969 (Reactome)
Planar gap junction plaques associated with Dab2 and Dynamin			REACT_9971 (Reactome)
			REACT_10004 (Reactome)	Insertion of a connexon into the cell membrane results in the formation of a hemi-channel. This channel permits direct exchanges between cell cytoplasm and extracellular matrix (Figure 3). Freeze-fracture electron microscopy studies have revealed that cytoplasmic vesicles can fuse with the plasma membrane to permit connexon insertion (Shivers and Bowman 1985). Hemi-channels appear to play a role in isosmotic cell volume regulation (Quist et al., 2000), in apoptosis regulation (Contreras et al. 2002; John et al. 1999), and in the differentiation of different cell types (Boucher and Bennett 2003). Individual connexons have been observed dispersed around gap junction plaques. This observation suggests that there is a pool of connexons dispersed in the plasma membrane which can migrate to gap junction plaques (Benedetti et al. 2000; Hulser et al. 1997; Lauf et al. 2002; Gaietta et al. 2002).
			REACT_10011 (Reactome)	One mechanism of transport of connexon-containing vesicles involves movement along microtubules (Segretain and Falk, 2004). Such a transport system has been described for similar secretory vesicles (Toomre et al., 1999). Direct microtubule-dependent transport of connexons to GJ-assembly sites has recently been reported as well (Shaw et al., 2007).
			REACT_10046 (Reactome)	Once transported to the plasma membrane, junctional channels aggregate into clusters forming gap junction plaques that may contain a few to many thousands of individual channels and that vary in size from a few square nanometers to many square micrometers (Bruzzone et al. 1996; Falk 2000; Severs et al. 2001). Gap junction plaques are involved in numerous processes including growth and differentiation (Loewenstein and Rose 1992), pathological cell proliferation (Roger et al. 2004; Segretain et al. 2003) and spermatogenesis (Juneja et al. 1999; Plum et al. 2000). The physiological importance of gap junction plaques is underscored by the diverse pathologies associated with connexin gene mutations (De Maio et al. 2002). An arbitrary number (10) of channels is shown as aggregating in this reaction but the actual number may be hundreds to thousands.
			REACT_10060 (Reactome)	Connexin-interacting proteins appear to function in regulating gap junction formation and communication. ZO-1 has been shown to alter the membrane localization of Cx43 and plays a role in regulating Cx43-mediated gap junctional communication in osteoblastic cells (Laing et al. 2005). ZO-1 may function in the delivery of Cx43 from a lipid raft domain to gap junctional plaques, which may be an important regulatory step in gap junction formation.
			REACT_10083 (Reactome)	Internalized GJ plaques are degraded by lysosomes. Lysosomal degradation appears to be the most common pathway of GJ degradation. (Qin et al., 2003; Grinzberg and Gilula., 1979 ; Berthoud et al., 2004 ; and Leithe et al., 2006).
			REACT_10108 (Reactome)	Docking of Cx43 at the plasma membrane may involve ZO-1 as well as alpha- and beta-catenin (Shaw et al., 2007). The role of ZO-1 in regulating gap junction biology is unclear. Recent results indicate a role for ZO-1 in regulating gap junction plaque size (Hunter et al., 2007).
			REACT_10110 (Reactome)	Connexon-containing transport vesicles have been shown to emanate from the Golgi and deliver connexons to the plasma membrane (Lauf et al., 2002).
			REACT_10125 (Reactome)	The closure of Cx43 gap junction channels is observed following src-mediated Cx43 phosphorylation.
			REACT_115750 (Reactome)	Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994). Cx26 has also been reported to insert post-translationally into the ER membrane (Zhang et al., 1996; Ahmad et al., 1999 ; Ahmad and Evans, 2002).
			REACT_21353 (Reactome)	Connexons may also traffic using a microtubule-independent mechanism. A few studies suggest that rough ER membranes can directly transfer connexons to the plasma membrane (Martin et al. 2001; Bloom and Goldstein 1998). Other cytoskeletal components, such as actin filaments, might be involved in the delivery of connexons to gap junction plaques (Thomas et al. 2001; Gilleron et al. 2006).
			REACT_9410 (Reactome)	Connexins (Cxs) are encoded by a large gene family predicted to include at least 20 isoforms in humans. Most mammalian Cx genes consist of two exons. The first consists of untranslated sequence, and the second contains the entire coding sequence. Exceptionally, Cx36 and Cx45 contain 3 exons and 2 introns and the third exon contains the coding sequence (Belluardo et al. 1999 ; Jacob and Beyer 2001). Connexins have been divided in two major subgroups, alpha and beta, according to their amino acid sequence similarity (see Bruzzone et al., 2001; Willecke et al., 2002). Alternative names and additional subgroups have been suggested as well. Cx are synthesized by ribosomes in the endoplasmic reticulum (ER) membrane. All Cx proteins contain four trans-membrane domains (TM1 to TM4), two extracellular loops (E1 and E2) and one cytoplasmic loop. The amino- and carboxyl termini are located in the cytosol (reviewed in Segretain and Falk, 2004). After targeting to the ER, connexins are checked by a quality control system to prevent misfolded forms from progressing through the secretory pathway. Aberrant proteins are removed by endoplasmic-reticulum-associated degradation (ERAD).
			REACT_9415 (Reactome)	A study using cultured cells demonstrated connexon oligomerization from Cx43 subunits inside the Trans-Golgi Network after exit from the ER (Musil and Goodenough 1993).
			REACT_9442 (Reactome)	Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994).
			REACT_9473 (Reactome)	Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994). It has been observed, however, that the oligomerization of Cx43 into connexons does not occur before the Trans-Golgi network (Musil and Goodenough, 1993; Koval, 2006).
			REACT_9494 (Reactome)	Studies using microsomes have revealed that oligomerization of connexins Cx26, Cx43, and Cx32 can occur after insertion of connexins in the ER membrane (Falk et al. 1997; Ahmad et al. 1999, Ahmad and Evans, 2002).
			REACT_9499 (Reactome)	Transport of connexins along the secretory pathway (including transit from the Golgi to the TGN where Cx43 is predicted to oligomerize) occurs in vesicular transport containers.
			REACT_9503 (Reactome)	Transport of connexins along the secretory pathway (including transit from the ER to the ERGIC where Cx32 is predicted to oligomerize) occurs in vesicular transport containers.
			REACT_9520 (Reactome)	Oligomerization of connexins Cx32 and Cx26 has also been observed in the ER-Golgi-intermediate compartment (ERGIC) (Diez et al. 1999). Heteromeric connexons containing both Cx32 and Cx26 have been observed. For the sake of simplicity, the connexon here is described as containing equal numbers of Cx26 and Cx32 subunits, although the ratio may vary.
			REACT_9951 (Reactome)	Dab2 is recruited to Cx43-based GJs possibly through a direct interaction between its N-terminal phosphotyrosine binding (PTB) domain and a putative XPXY internalization motif found in the C-terminal tail of Cx43 as well as a number of other connexin family members (Piehl et al., 2007).The distal portion of Dab2 on its opposite end binds the globular N-terminal domain of clathrin heavy chains (Piehl et al., 2007).
			REACT_9969 (Reactome)	The GTPase dynamin, which functions in the completion of vesicle budding localizes in Cx43-based GJs and especially invaginating plaques and AGJ vesicles (Piehl et al., 2007).
			REACT_9971 (Reactome)	GJ plaques, clusters of GJ channels, can be internalized to form large, double-membrane vesicles (aka AGJs). Internalized AGJ vesicles subdivide into smaller vesicles that are subsequently degraded by endo/lysosomal pathways (Piehl et al., 2007).
			REACT_9975 (Reactome)	c-src has been shown to interact with Cx43 (Giepmans et al., 2001). Models describing v-src mediated Cx43 channel gating propose that the initial interaction between v-src and Cx43 may occur via a SH3 domain interaction (see Lau 2005).
			REACT_9990 (Reactome)	Junctional channels are an assembly of two docked connexons on adjacent cells that permits direct communication of the cytoplasm in the two cells as shown below. Proteins associated with GJs such as catenins (Wu et al., 2003, Shaw et al., 2007) and L-CAM (Musil et al., 1990) might be required for connexon docking. Docking occurs through a tight interaction of the extracellular loops (Unger et al., 1999; Sosinsky and Nicholson, 2005). Intramolecular disulfide bridges between the two extracellular loops (E1 and E2) of connexin polypeptides are important for the correct three-dimensional structure of the extracellular loops (Foote et al., 1998)
			REACT_9997 (Reactome)	c-Src phosphorylates Cx43 on Tyr 265.
SRC-2			REACT_9975 (Reactome)
TJP1			REACT_10060 (Reactome)
c-src-associated Cx43 junctional channel			REACT_10125 (Reactome)
	closed Cx43 junctional channel	Arrow	REACT_10125 (Reactome)
	connexons in Golgi transport vesicle docked to microtubules	Arrow	REACT_10011 (Reactome)
connexons in Golgi transport vesicle docked to microtubules			REACT_10108 (Reactome)
	gap junction plaque	Arrow	REACT_10046 (Reactome)
	microtubule	Arrow	REACT_10004 (Reactome)
microtubule			REACT_10011 (Reactome)
	phospho-Y265 Cx43:ZO-1 gap junction	Arrow	REACT_9997 (Reactome)
	planar gap junction plaques associated with Dab2	Arrow	REACT_9951 (Reactome)
planar gap junction plaques associated with Dab2			REACT_9969 (Reactome)
planar gap junction plaques			REACT_9951 (Reactome)