A-kinase anchor proteins in endocrine system and reproduction

Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 01/2002; 12(10):434-40. DOI: 10.1016/S1043-2760(01)00493-3
Source: PubMed


Over the past few years, significant progress has been made in characterizing the expression and localization of proteins that act as scaffolds for cAMP-dependent protein kinase (PK-A). These A-kinase anchor proteins (AKAPs) tether PK-A to intracellular organelles and structures, sequestering the kinase near its physiological substrates. The compartmentalization of distinct pockets of PK-A activity serves to provide spatial regulation of this signaling pathway. In addition, other signaling proteins bind to AKAPs, as do some newly described proteins of unknown function, suggesting that proteins of various pathways are anchored through AKAPs.

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    • "In S. aurata, an AKAP protein that anchors the regulatory subunit of PKA for tethering of protein kinases in close proximity to their target proteins has been identified. Different types of AKAP have been found in spermatozoa, localized into the fibrous sheath of the principal piece (Moss and Gerton 2001). In mammals, it has been demonstrated that, among the proteins phosphorylated during epididymal maturation, there are several mitochondrial proteins (Aitken et al. 2007) and a protein phospahatase PP1γ2 (Chakrabarti et al. 2007). "
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    ABSTRACT: In many marine fish species, the spermatozoa are immotile in the testis and seminal plasma, and motility is induced when they are released in the aqueous environment. It is well known that the extracellular factors (hyperosmolality or sperm-activating peptides), controlling sperm motility in marine fish, act on the axonemal apparatus through signal transduction across the plasma membrane. To better understand the molecular mechanism regulating axoneme activation in marine fish, the present review examines the existing literature, with particular emphasis on protein phosphorylation/dephosphorylation process. The present review suggests that: (1) there is no single model that can explain the molecular activation and regulation of sperm motility of the marine fish; (2) only in some species (puffer fish, tilapia, gilthead sea bream, and striped sea bream) protein phosphorylation/dephosphorylation has been shown to be involved in flagellar motility regulation; (3) only a few proteins were identified, which show a change in their state of phosphorylation following sperm activation. A model of molecular mechanism controlling the activation of sperm motility in gilthead sea bream is being proposed here, which could be a useful model to clarify the sperm motility activation process in other species.
    International Aquatic Research 06/2012; 4(1). DOI:10.1186/2008-6970-4-2
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    • "PRKG1 functions directly as a redox sensor directly activated by oxidation in vitro, and in rat cells and tissues [34]. This oxidation-induced activation represents an alternate mechanism for regulation along with the classic activation involving nitric oxide and cGMP; (c) AKAP6, a member of the cAMP dependent protein kinase (PKA) anchoring proteins family [35] located on the endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). AKAP6 is selectively expressed in brain, cardiac and skeletal muscle [36] and it is specifically localized in the SR, therefore, sequestering PKA to this organelle [36]; and (d) SGCD, a member of Sarcoglycan family critical in linking cytoskeleton to extracellular matrix. "
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    ABSTRACT: Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33-34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca(2+) signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis.
    PLoS ONE 09/2010; 5(9):e12601. DOI:10.1371/journal.pone.0012601 · 3.23 Impact Factor
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    • "So far, cAMP/PKA seems to play a key role in the mechanisms that trigger capacitation and the associated P-Tyr in all the mammalian species studied [11,26,27,72,88–91]. Of interest, the proteins subjected to P-Tyr during capacitation are AKAPs and the major proteins of the fibrous sheath, the cytoskeletal structure surrounding the axoneme and outer dense fibers of mammalian sperm flagellum [17] [92] [93]. AKAPs act as scaffolds for signaling elements, such as PKA, calmodulin, and PKC [94]. "
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    ABSTRACT: The role of reactive oxygen species (ROS) as signal transduction elements in physiological phenomena is a recent concept that changes the paradigm of these active species as harmful molecules that promote deleterious effects and even cell death. Capacitation is a term used to define a complex and not well-characterized process that allows spermatozoa to complete their preparation to fertilize oocytes. Spermatozoa from many species incubated under specific conditions have the ability to produce small amounts of ROS without harming cell function and rather promoting signal transduction pathways associated with capacitation. This review summarizes the findings regarding the role of ROS during mammalian sperm capacitation, specifically as physiological mediators that trigger phosphorylation events. The role of ROS as regulators of protein tyrosine phosphorylation has been known for a decade but other novel phosphorylations, such as those of PKA substrates, of MEK-like proteins, and of proteins with the threonine-glutamine-tyrosine motif, were recently evidenced. Here we stress the involvement of PKA and the ERK pathway as two signal mechanisms acting independently that contribute to the modulation of protein tyrosine phosphorylation required for spermatozoa to achieve capacitation. Moreover, integration of all these data reinforces the concept that although some phosphorylation events are independent of the others, cross talk is also needed among the various pathways involved.
    Free Radical Biology and Medicine 09/2006; 41(4):528-40. DOI:10.1016/j.freeradbiomed.2006.04.027 · 5.74 Impact Factor
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