NCBI Summary:
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in 2 transcript variants encoding 2 isoforms with different sizes. Both of the isoforms bind to types I and II regulatory subunits of PKA and anchor them to mitochondria. As compared to the longer isoform, the shorter isoform lacks a K-homologous motif, which is an RNA-binding domain typically associated with proteins involved in RNA catalysis, mRNA processing, or translation. The longer isoform is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. The function of the shorter isoform has not been determined.
General function
Nucleic acid binding, RNA binding
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Cellular localization
Cytoplasmic, Nuclear
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Ovarian function
Oocyte maturation
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A-Kinase Anchor Protein 1 (AKAP1) Regulates cAMP-Dependent Protein Kinase (PKA) Localization and Is Involved in Meiotic Maturation of Porcine Oocytes. Nishimura T et al. In mammalian oocytes, cAMP-dependent protein kinase (PKA) has critical functions in meiotic arrest and meiotic maturation. Although it is known that subcellular localization of PKA is regulated by A-kinase anchor proteins (AKAPs) and that PKA compartmentalization is essential for PKA functions, the role of AKAPs in meiotic regulation has not been fully elucidated. In the present study, we performed far-Western blotting using porcine PRKAR2A for detection of AKAPs and found several signals in porcine oocytes for the first time. Among these signals, a 150 kDa-AKAP showed the major expression; we found this AKAP to be the product of porcine AKAP1. Overexpression of AKAP1 changed the PKA localization and promoted meiotic resumption of porcine oocytes even in the presence of a high concentration of cAMP, which inhibits meiotic resumption by inducing high PKA activity. On the contrary, knockdown of AKAP1 showed inhibitory effects on meiotic resumption and oocyte maturation. We also revealed that the expression level of AKAP1 in porcine growing oocytes, which show meiotic incompetence and PKA mislocalization, was significantly lower than that of fully grown oocytes. However AKAP1 insufficiency was not the primary cause of the meiotic incompetence of the growing oocytes. These results suggest the possibility that the regulation of PKA localization by AKAP1 is involved in the meiotic resumption and oocyte maturation but not in the meiotic incompetence of porcine growing oocytes.
Dynamic Anchoring of PKA Is Essential during Oocyte Maturation Newhall KJ,et al .
In the final stages of ovarian follicular development, the mouse oocyte remains arrested in the first meiotic prophase, and cAMP-stimulated PKA plays an essential role in this arrest. After the LH surge, a decrease in cAMP and PKA activity in the oocyte initiates an irreversible maturation process that culminates in a second arrest at metaphase II prior to fertilization . A-kinase anchoring proteins (AKAPs) mediate the intracellular localization of PKA and control the specificity and kinetics of substrate phosphorylation . Several AKAPs have been identified in oocytes including one at 140 kDa that we now identify as a product of the Akap1 gene. We show that PKA interaction with AKAPs is essential for two sequential steps in the maturation process: the initial maintenance of meiotic arrest and the subsequent irreversible progression to the polar body extruded stage. A peptide inhibitor (HT31) that disrupts AKAP/PKA interactions stimulates oocyte maturation in the continued presence of high cAMP. However, during the early minutes of maturation, type II PKA moves from cytoplasmic sites to the mitochondria, where it associates with AKAP1, and this is shown to be essential for maturation to continue irreversibly.
Expression regulated by
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Ovarian localization
Oocyte
Comment
A-kinase anchoring proteins (AKAPs) mediate the intracellular localization of protein kinase A (PKA) and affect downstream signaling events. The A-kinase anchoring protein, AKAP1 (S-AKAP84, D-AKAP1), localizes PKA to the mitochondria of elongating spermatids, and disruption of the PKA-AKAP complex is reported to decrease sperm motility. In addition, AKAPs have been identified in ovarian cells, including the oocyte, and AKAP1 is expressed in the ovary.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Endocrine society 2004
[OR14-6] AKAP1 Is Dispensable for Male Fertility, but Required for Resumption of Meiosis during Oocyte Maturation in the Female.
Kathryn J MacLean, Katherine E Kafer, G Stanley McKnight. Pharmacology, Univ of Washington, Seattle, WA
The gene for AKAP1 was deleted by homologous recombination in embryonic stem cells. The knockout (KO) mice are indistinguishable from their wildtype (WT) littermates in body weight and overall appearance. Male reproductive status is not significantly compromised as a result of deletion of the AKAP1 gene. Fertility, total sperm count, and sperm motility are unchanged between WT and KO mice. Histological examination of the testis did not indicate differences between WT and KO mice at any stage of germ cell development. In addition, the loss of AKAP1 does not change PKA subunit expression or localization in mature sperm. However, female AKAP1 KO mice are subfertile. KO females have a 65% reduction in the number of litters and a 75% reduction in litter size compared to WT mice. Ovaries from AKAP1 KO mice appear normal, and these females release the same number of oocytes upon superovulation as their WT littermates. However, eggs from KO females that were fertilized in vivo do not reach the two-cell stage due to a defect in germinal vesicle breakdown (GVBD). Kinase assays indicate that GV-stage oocytes from AKAP1 KO females have increased PKA activity, and the defect in GVBD can be reversed in vitro with inhibitors of PKA. Furthermore, KO oocytes show constitutive phosphorylation of Cdc25b phosphatase, which is required for MPF activation and resumption of meiosis in mouse oocytes. Phosphorylation of Cdc25b by PKA inactivates it and prevents GVBD. Our working hypothesis is that AKAP1 plays a role in reducing PKA activity or sequestering it from substrates such as Cdc25b that are required for resumption of meiosis in the oocyte.