Association of Connexin43 with a Receptor Protein Tyrosine Phosphatase

Giepmans, Ben N. G.; Feiken, Elles; Gebbink, Martijn F.B.G.; Moolenaar, Wouter H.

doi:10.1080/714040427

Cited by 9 publications

(10 citation statements)

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“…Accumulating data have demonstrated a direct interaction of the Cx43 C-terminus, with cytoskeletal proteins displaying signal transduction activity, including drebrin (Butkevich et al, 2004), ZO-1 (zonula occludens 1 (Toyofuku et al, 2001), and c-Src (Giepmans et al, 2003). Therefore, we analyzed the ability of the mutated and wildtype protein to interact with the cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Induces Myoblast Differentiation through Cx43 Protein Expression: A Role for a Gap Junction-dependent and -independent Function

Squecco

Sassoli²,

Nuti

et al. 2006

MBoC

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Although sphingosine 1-phosphate (S1P) has been considered a potent regulator of skeletal muscle biology, acting as a physiological anti-mitogenic and prodifferentiating agent, its downstream effectors are poorly known. In the present study, we provide experimental evidence for a novel mechanism by which S1P regulates skeletal muscle differentiation through the regulation of gap junctional protein connexin (Cx) 43. Indeed, the treatment with S1P greatly enhanced Cx43 expression and gap junctional intercellular communication during the early phases of myoblast differentiation, whereas the down-regulation of Cx43 by transfection with short interfering RNA blocked myogenesis elicited by S1P. Moreover, calcium and p38 MAPK-dependent pathways were required for S1P-induced increase in Cx43 expression. Interestingly, enforced expression of mutated Cx43⌬130 -136 reduced gap junction communication and totally inhibited S1P-induced expression of the myogenic markers, myogenin, myosin heavy chain, caveolin-3, and myotube formation. Notably, in S1P-stimulated myoblasts, endogenous or wild-type Cx43 protein, but not the mutated form, coimmunoprecipitated and colocalized with F-actin and cortactin in a p38 MAPK-dependent manner. These data, together with the known role of actin remodeling in cell differentiation, strongly support the important contribution of gap junctional communication, Cx43 expression and Cx43/cytoskeleton interaction in skeletal myogenesis elicited by S1P.

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Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Induces Myoblast Differentiation through Cx43 Protein Expression: A Role for a Gap Junction-dependent and -independent Function

Squecco

Sassoli²,

Nuti

et al. 2006

MBoC

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“…Because bisphosphonate binding to osteoblastic cells was displaced by protein phosphatase substrates [10] the putative target molecule which links BPs with Cx43 could be a phosphatase. Interestingly, recent studies have shown that PTP interacts with the regulatory C-terminal tail of Cx43 [20].…”

Section: Discussionmentioning

confidence: 99%

Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways

Lezcano

Boland

Morelli

2011

Bone

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Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [ 3 H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na 3 VO 4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.

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“…The phosphatases acting upon and regulating the activities of connexin-43 have been also long sought after. Receptor protein tyrosine phosphatase  (RPTP) has been suggested to dephosphorylate Tyr residues present in connexin-43 in lung cells (Giepmans et al, 2003), however, its physiological relevance in the myocardium remains to be established. Moreover, serine/threonine phosphatase type 1 and type 2A (PP1 and PP2A, respectively) have been implicated in the dephosphorylation of connexin-43 (Ai and Pogwizd, 2005;Duthe et al, 2001;Jeyaraman et al, 2003).…”

Section: Phosphorylation Regulates the Permeability Of Connexonsmentioning

confidence: 99%