Differential regulation of Connexin50 and Connexin46 by PI3K signaling

Martinez, Jennifer M.; Wang, Hong-Zhan; Lin, Richard Z.; Brink, Peter R.; White, Thomas W.

doi:10.1016/j.febslet.2015.04.029

Cited by 16 publications

(16 citation statements)

References 45 publications

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“… 35 , 38 , 39 , 46 Interestingly, Cx50 has the greatest level of functional activity in epithelial cells in the early postnatal period when lens mitosis switches to the pulsatile growth pattern, and Cx50 conductance can be upregulated by p110α activity. 39 , 47 Thus, one possibility is the absence of p110α results in a delay in the upregulation of Cx50 gap junction channels in epithelial cells at P0, producing a transient decrease in germinative zone proliferation. The availability of a lens-specific p110α knockout mouse model will allow future testing of this hypothesis through interbreeding with Cx50-deficient mice to test for functional epistasis.…”

Section: Discussionmentioning

confidence: 99%

The Phosphoinosotide 3-Kinase Catalytic Subunit p110α is Required for Normal Lens Growth

Sellitto

Vaghefi

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeSignal transduction pathways influence lens growth, but little is known about the role(s) of the class 1A phosphoinositide 3-kinases (PI3Ks). To further investigate how signaling regulates lens growth, we generated and characterized mice in which the p110α and p110β catalytic subunits of PI3K were conditionally deleted in the mouse lens.MethodsFloxed alleles of the catalytic subunits of PI3K were conditionally deleted in the lens by using MLR10-cre transgenic mice. Lenses of age-matched animals were dissected and photographed. Postnatal lenses were fixed, paraffin embedded, sectioned, and stained with hematoxylin-eosin. Cell proliferation was quantified by labeling S-phase cells in intact lenses with 5-ethynyl-2′-deoxyuridine. Protein kinase B (AKT) activation was examined by Western blotting.ResultsLens-specific deletion of p110α resulted in a significant reduction of eye and lens size, without compromising lens clarity. Conditional knockout of p110β had no effect on lens size or clarity, and deletion of both the p110α and p110β subunits resulted in a phenotype that resembled the p110α single-knockout phenotype. Levels of activated AKT were decreased more in p110α- than in p110β-deficient lenses. A significant reduction in proliferating cells in the germinative zone was observed on postnatal day 0 in p110α knockout mice, which was temporally correlated with decreased lens volume.ConclusionsThese data suggest that the class 1A PI3K signaling pathway plays an important role in the regulation of lens size by influencing the extent and spatial location of cell proliferation in the perinatal period.

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Section: Discussionmentioning

confidence: 99%

The Phosphoinosotide 3-Kinase Catalytic Subunit p110α is Required for Normal Lens Growth

Sellitto

Vaghefi

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…This phosphorylation site might therefore act as a molecular switch to increase GJIC under these conditions [ 44 ]. A potential regulation of Cx50 but not Cx46 by PI3K signaling has been described in a study of Martínez and colleagues [ 45 ]. They demonstrated that PI3K/AKT activation upregulated Cx50 GJ conductance whereas inhibition of PI3K or AKT decreased Cx50 mediated GJ conductance [ 45 ].…”

Section: Regulation Of Gjs and Hcs By Phosphorylationmentioning

confidence: 98%

Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision

et al. 2016

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Post-translational modifications of connexins play an important role in the regulation of gap junction and hemichannel permeability. The prerequisite for the formation of functional gap junction channels is the assembly of connexin proteins into hemichannels and their insertion into the membrane. Hemichannels can affect cellular processes by enabling the passage of signaling molecules between the intracellular and extracellular space. For the intercellular communication hemichannels from one cell have to dock to its counterparts on the opposing membrane of an adjacent cell to allow the transmission of signals via gap junctions from one cell to the other. The controlled opening of hemichannels and gating properties of complete gap junctions can be regulated via post-translational modifications of connexins. Not only channel gating, but also connexin trafficking and assembly into hemichannels can be affected by post-translational changes. Recent investigations have shown that connexins can be modified by phosphorylation/dephosphorylation, redox-related changes including effects of nitric oxide (NO), hydrogen sulfide (H2S) or carbon monoxide (CO), acetylation, methylation or ubiquitination. Most of the connexin isoforms are known to be phosphorylated, e.g. Cx43, one of the most studied connexin at all, has 21 reported phosphorylation sites. In this review, we provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation. Regarding the effects of oxidants we discuss the role of NO in different cell types and tissues and recent studies about modifications of connexins by CO and H2S.

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“…The interaction of Skp2 with Cx50 at the plasma membrane is thought to mask the nuclear localization signal of Skp2, blocking nuclear translocation and leading to the stabilization of p27 kip1 and p57 kip2 . The PI3K pathway has been implicated in Cx50 regulation, with increased PI3K signaling leading to specific increases in Cx50-mediated coupling (Martinez et al, 2015). Similarly, lens specific knockout of p110α (the catalytic subunit of PI3K) leads to a reduction in cell-cell coupling, reduced proliferation and a microphakic phenotype similar to that seen in Gja8 -null lenses (Sellitto et al, 2016).…”

Section: Molecular Genetic Insights Into Lens Growth Regulationmentioning

confidence: 99%

The lens growth process

Bassnett

Šikić

2017

Progress in Retinal and Eye Research

102

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The factors that regulate the size of organs to ensure that they fit within an organism are not well understood. A simple organ, the ocular lens serves as a useful model with which to tackle this problem. In many systems, considerable variance in the organ growth process is tolerable. This is almost certainly not the case in the lens, which in addition to fitting comfortably within the eyeball, must also be of the correct size and shape to focus light sharply onto the retina. Furthermore, the lens does not perform its optical function in isolation. Its growth, which continues throughout life, must therefore be coordinated with that of other tissues in the optical train. Here, we review the lens growth process in detail, from pioneering clinical investigations in the late nineteenth century to insights gleaned more recently in the course of cell and molecular studies. During embryonic development, the lens forms from an invagination of surface ectoderm. Consequently, the progenitor cell population is located at the surface and differentiated cells are confined to the interior. The interactions that regulate cell fate thus occur within the obligate ellipsoidal geometry of the lens. In this context, mathematical models are particularly appropriate tools with which to examine the growth process. In addition to identifying key growth determinants, such models constitute a framework for integrating cell biological and optical data, helping clarify the relationship between gene expression in the lens and image quality at the retinal plane.

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Differential regulation of Connexin50 and Connexin46 by PI3K signaling

Cited by 16 publications

References 45 publications

The Phosphoinosotide 3-Kinase Catalytic Subunit p110α is Required for Normal Lens Growth

The Phosphoinosotide 3-Kinase Catalytic Subunit p110α is Required for Normal Lens Growth

Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision

The lens growth process

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