Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelination within the central nervous system (CNS) involves substantial morphogenesis of oligodendrocytes requiring plastic changes in oligodendrocyte-extracellular matrix (ECM) interactions, that is, adhesion. Our previous studies indicated that a regulator of such adhesive plasticity is oligodendrocyte-released phosphodiesterase-I alpha/autotaxin (PD-I alpha/ATX). We report here, that PD-I alpha/ATX's adhesion antagonism is mediated by a protein fragment different from the one that stimulates tumor cell motility. Furthermore, PD-I alpha/ATX's adhesion-antagonizing fragment causes a reorganized distribution of the focal adhesion components vinculin and paxillin and an integrin-dependent reduction in focal adhesion kinase (FAK) phosphorylation at tyrosine residue 925 (pFAK-925). In vivo, a similar reduction in pFAK-925 occurs at the onset of myelination when PD-I alpha/ATX expression is significantly upregulated. Most importantly, it can also be induced by the application of exogenous PD-I alpha/ATX. Our data, therefore, suggest that PD-I alpha/ATX participates in the regulation of myelination via a novel signaling pathway leading to changes in integrin-dependent focal adhesion assembly and consequently oligodendrocyte-ECM interactions.
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PMID:Phosphodiesterase-I alpha/autotaxin controls cytoskeletal organization and FAK phosphorylation during myelination. 1548 70

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
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PMID:Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. 1588 25

Premature ejaculation is a common sexual problem which presents to genitourinary (GU) medicine services. Five main treatment approaches have been used in clinical trials: behavioural therapy, antidepressants, phosphodiesterase-5 (PDE5) inhibitors, topical anaesthetic agents and alpha-blockers. We have carried out a systematic review of published pharmacological trials. All antidepressants appeared to delay ejaculation to some extent at all doses. Anaesthetic creams appeared to be as successful in slowing ejaculation as antidepressants without systemic side-effects, although some patients did experience erectile problems or unpleasant local symptoms. Anecdotally, behavioural therapy is effective and appears to have long-lasting efficacy. There is a need for quality comparative trial of behavioural therapy, topical anaesthetic agents and antidepressants, including appropriate measures of relapse, follow-up and acceptability of continuing long-term treatment.
Int J STD AIDS 2005 Oct
PMID:A review of controlled trials in the pharmacological treatment of premature ejaculation. 1621 10

Premature ejaculation is a common male sexual dysfunction. Treatment modalities as recommended by the British Association of Sexual Health and HIV include behavioural therapy, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and local anaesthetic creams. We audited the clinical cohort from our dedicated sexual dysfunction clinic to determine the success of prescribed treatment and co-existing prostatitis/male pelvic pain, erectile dysfunction, phosphodiesterase-5 (PDE5) inhibitor use and anxiety. The use of SSRIs was successful in the treatment of premature ejaculation with or without the use of local anaesthetic cream. Co-existing prostatitis/male pelvic pain, erectile dysfunction, PDE5 inhibitor use and anxiety were high.
Int J STD AIDS 2005 Oct
PMID:Pharmacological treatment for premature ejaculation. 1621 22

The term 'female sexual dysfunction' (FSD) encompasses a number of different disorders, and while their aetiologies are not fully understood, the sub-classifications of this broad umbrella term are increasingly becoming more established and accepted. However, there is less consensus regarding the optimal treatment of these conditions. While it is known that phosphodiesterase (PDE5) is involved in the female sexual response, the clinical and research evidence supporting the unlicensed use of PDE5 inhibitors (PDE5i) in women is inconclusive and at times contradictory. In this article we explore this further by means of a comprehensive literature review on the use of PDE5i in the treatment of FSD and we also present our clinical experience of using these drugs in this context.
Int J STD AIDS 2009 Mar
PMID:A literature review and case reports series on the use of phosphodiesterase inhibitors in the treatment of female sexual dysfunction. 1945 38

The elevation of [cAMP](i) is an important mechanism of platelet inhibition and is regulated by the opposing activity of adenylyl cyclase and phosphodiesterase (PDE). In this study, we demonstrate that a variety of platelet agonists, including thrombin, significantly enhance the activity of PDE3A in a phosphorylation-dependent manner. Stimulation of platelets with the PAR-1 agonist SFLLRN resulted in rapid and transient phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492), in parallel with the PKC (protein kinase C) substrate, pleckstrin. Furthermore, phosphorylation and activation of PDE3A required the activation of PKC, but not of PI3K/PKB, mTOR/p70S6K, or ERK/RSK. Activation of PKC by phorbol esters also resulted in phosphorylation of the same PDE3A sites in a PKC-dependent, PKB-independent manner. This was further supported by the finding that IGF-1, which strongly activates PI3K/PKB, but not PKC, did not regulate PDE3A. Platelet activation also led to a PKC-dependent association between PDE3A and 14-3-3 proteins. In contrast, cAMP-elevating agents such as PGE(1) and forskolin-induced phosphorylation of Ser(312) and increased PDE3A activity, but did not stimulate 14-3-3 binding. Finally, complete antagonism of PGE(1)-evoked cAMP accumulation by thrombin required both G(i) and PKC activation. Together, these results demonstrate that platelet activation stimulates PKC-dependent phosphorylation of PDE3A on Ser(312), Ser(428), Ser(438), Ser(465), and Ser(492) leading to a subsequent increase in cAMP hydrolysis and 14-3-3 binding.
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PMID:Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. 1926 11

Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
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PMID:Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL. 1936 27

Female sexual dysfunction (FSD) incorporates various sexual disorders including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic and sexual pain disorders. Although many strategies have been formulated for the treatment of male sexual problems, FSD remains an area that warrants further research and trial studies to identify the most efficacious treatment options. Research has highlighted numerous pharmacological interventions that have been trialled and found to exhibit positive effects. These include hormonal therapies, prostaglandins, dopaminergic agonists, phosphodiesterase type-5 (PDE-5) inhibitors and melanocortin agonists.
Int J STD AIDS 2009 Oct
PMID:Review of drug treatment for female sexual dysfunction. 1981 9

Premature ejaculation (PE) is the most common male sexual problem worldwide affecting 22-38% of men. It has a significant morbidity both on patients and their partners, causing distress, anxiety and relationship difficulties. The mainstay of treatment is a combined approach using behavioural therapies and non-licensed medication such as topical anaesthetic preparations, selective serotonin re-uptake inhibitors and phosphodiesterase-5 inhibitors. In recent years, there has been a greater emphasis placed on researching novel treatments and exploring the on-demand use of current preparations. This review provides an overview of current accepted treatments and emerging agents for the use in PE.
Int J STD AIDS 2010 Feb
PMID:Premature ejaculation: treatment update. 2008 91

Ligation of both the T cell receptor (TCR) and the CD28 receptor is required for full T cell activation to occur. Engagement of the TCR in primary T cells is followed by rapid cAMP production in lipid rafts and activation of the cAMP-protein kinase A (PKA)-Csk pathway inhibiting proximal T cell signaling. However, CD28 stimulation leads to recruitment of a beta-arrestin/phosphodiesterase-4 (PDE4) complex to rafts, resulting in down-regulation of cAMP levels. Thus, the activities of both PKA and PDE4 seem to be important for regulation of TCR-induced signaling and T cell function. This review will focus on the novel mechanism whereby CD28 through PI3K regulates recruitment of a PKB/beta-arrestin/PDE4 complex thereby allowing a complete T cell activation to proceed.
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PMID:Novel mechanism of signaling by CD28. 2012 10


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