Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

Jacobsen, Nicole L.; Pontifex, Tasha K.; Li, Hanjun; Solan, Joell L.; Lampe, Paul D.; Sorgen, Paul L.; Burt, Janis M.

doi:10.1242/jcs.202572

Cited by 25 publications

(60 citation statements)

References 59 publications

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“…This anti-proliferative effect of Cx37 was first shown by Burt et al [ 118 ], where induced expression of Cx37 delayed cell cycle progression and reduced proliferation in rat insulinoma cells [ 118 ]. A possible mechanism explaining this anti-proliferative effect is through differential phosphorylation of Cx37 CT regulating gap junctional conductance, with reduced gap junctional conductance being associated with both reduced proliferation and apoptosis in rat insulinoma cells [ 119 ].…”

Section: Connexins and Endothelial Cellsmentioning

confidence: 99%

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

Johnson

Camelliti

2018

IJMS

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The heart is a complex organ composed of multiple cell types, including cardiomyocytes and different non-myocyte populations, all working closely together to determine the hearts properties and maintain normal cardiac function. Connexins are abundantly expressed proteins that form plasma membrane hemichannels and gap junctions between cells. Gap junctions are intracellular channels that allow for communication between cells, and in the heart they play a crucial role in cardiac conduction by coupling adjacent cardiomyocytes. Connexins are expressed in both cardiomyocytes and non-myocytes, including cardiac fibroblasts, endothelial cells, and macrophages. Non-myocytes are the largest population of cells in the heart, and therefore it is important to consider what roles connexins, hemichannels, and gap junctions play in these cell types. The aim of this review is to provide insight into connexin-based signalling in non-myocytes during health and disease, and highlight how targeting these proteins could lead to the development of novel therapies. We conclude that connexins in non-myocytes contribute to arrhythmias and adverse ventricular remodelling following myocardial infarction, and are associated with the initiation and development of atherosclerosis. Therefore, therapeutic interventions targeting these connexins represent an exciting new research avenue with great potential.

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Section: Connexins and Endothelial Cellsmentioning

confidence: 99%

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

Johnson

Camelliti

2018

IJMS

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“…97 Phosphorylations have been studied best, though mainly in Cx43, 86,92 but some analogous studies have also been performed in other vascular connexins. 98 Several protein kinases, among them protein kinase A (PKA) 99 and protein kinase C (PKC), 61,100 mitogen-activated kinases (MAP kinases), 86 the protein kinase B (AKT) 101 and Src family kinases, 91 have been shown to phosphorylate one or several sites in the connexin C-terminus. For details, see following reviews: 56,86,92 Of note, the important role of phosphorylation implies a complementary role of phosphatases in the regulation of connexin functionalities.…”

Section: Regulatory Principlesmentioning

confidence: 99%

Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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Vascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells' responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel-independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.

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“…For example, activation of PKA decreases Cx45 and increases Cx43 junctional conductance (37,38), and activation of cGMP-dependent protein kinase has no effect on Cx45 but decreases Cx43 junctional conductance (37,38). Additionally, the response of Cx37 channels to PKC activation or inhibition is opposite to that observed for Cx43 gap junction channels (39).…”

Section: Discussionmentioning

confidence: 95%

Regulation of Connexin32 by ephrin receptors and T-cell protein-tyrosine phosphatase

Trease¹,

Spagnol³

et al. 2019

Journal of Biological Chemistry

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Gap junctions are intercellular conduits that permit the passage of ions, small metabolites, and signaling molecules between cells. Connexin32 (Cx32) is a major gap junction protein in the liver and brain. Phosphorylation is integral to regulating connexin assembly, degradation, and electrical and metabolic coupling, as well as to interactions with molecular partners. Cx32 contains two intracellular tyrosine residues, and tyrosine phosphorylation of Cx32 has been detected after activation of the epidermal growth factor receptor; however, the specific tyrosine residue and the functional implication of this phosphorylation remain unknown. To address the limited available information on Cx32 regulation by tyrosine kinases, here we used the Cx32 C-terminal (CT) domain in an in vitro kinase-screening assay, which identified ephrin (Eph) receptor family members as tyrosine kinases that phosphorylate Cx32. We found that EphB1 and EphA1 phosphorylate the Cx32CT domain residue Tyr 243 . Unlike for Cx43, the tyrosine phosphorylation of the Cx32CT increased gap junction intercellular communication. We also demonstrated that T-cell protein-tyrosine phosphatase dephosphorylates pTyr 243 . The data presented above along with additional examples throughout the literature of gap junction regulation by kinases, indicate that one cannot extrapolate the effect of a kinase on one connexin to another.Gap junctions are intercellular channels that permit the free passage of ions, small metabolites, and signaling molecules between neighboring cells. They are important for a number of physiological processes, including cell growth, differentiation, and synchronization. A major gap junction protein in the liver and brain, as well as in a number of other tissues, is Connexin32 (Cx32) 3 (1). Cx32-deficient mice have an increased chance of

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Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

Cited by 25 publications

References 59 publications

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

Connexins in the control of vasomotor function

Regulation of Connexin32 by ephrin receptors and T-cell protein-tyrosine phosphatase

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