Disease relevance of AKAP3

• High AKAP3 mRNA expression was observed in 15 ovarian cancer specimens (28 %) [1].
• AKAP-3 expression significantly correlated with increased likelihood of residual tumor (P = 0.005), but no increase in the likelihood of recurrence or persistent disease (P = 0.06) [2].

High impact information on AKAP3

• More than 60 phosphorylated sequences were then mapped by MS/MS, including precise sites of tyrosine and serine phosphorylation of the sperm tail proteins AKAP-3 and AKAP-4 [3].
• Using in vitro binding and coimmunoprecipitation assays, we have shown that only activated G alpha 13 binds to AKAP110, suggesting a potential role for AKAP110 as a G alpha subunit effector protein [4].
• These results demonstrate that PI 3-kinase negatively regulates sperm motility by interfering with AKAP3-PKA binding, providing the first evidence of a molecular mechanism by which PKA can be targeted to sperm tails by interaction with tyrosine phosphorylated form of AKAP3 [5].
• The increased binding of RIIbeta to AKAP3 induced by LY294002 is mainly due to tyrosine phosphorylation of AKAP3, since it is completely blocked by the tyrosine kinase inhibitor erbstatin, which also reverses the effects of LY294002 on motility and suppresses PKA-AKAP3 interaction [5].
• The requirement of PKA binding to AKAP3 for sperm motility is confirmed by the reduction of motility induced by an inhibitor of RIIbeta-AKAP3 binding, Ht31, whose effects on sperm motility and PKA binding to AKAP3 are reversed by LY294002 [5].

Biological context of AKAP3

• Molecular genetic analysis of two human sperm fibrous sheath proteins, AKAP4 and AKAP3, in men with dysplasia of the fibrous sheath [6].
• The gene encoding FSP95 has 5 exons separated by 4 introns and is located on chromosome 12 at locus p13 [7].
• We report the case of an infertile man with normal sperm count and total sperm immotility in which dysplasia of the fibrous sheath, Akap3, Akap4 gene deletions, meiotic segregation of chromosomes 18, X and Y and Y microdeletions were investigated [8].

Anatomical context of AKAP3

• A-kinase anchoring protein 3 (AKAP3) is a sperm protein and its expression appears to be restricted to the testis in normal adult tissues [1].
• The AKAP4 precursor is processed in the flagellum and only the mature form of AKAP4 appears to bind AKAP3 [9].
• AKAP3 is synthesized in round spermatids and incorporated into the fibrous sheath concurrently with formation of the rib precursors [9].
• CONCLUSIONS: As predicted by its N-terminal domain that is 45% identical to the human RIIalpha of PKA, Sp17 from spermatozoa binds the RII binding domain of AKAP3 along the length of the flagella [10].
• Cloning and characterization of SOB1, a new testis-specific cDNA encoding a human sperm protein probably involved in oocyte recognition [11].

Associations of AKAP3 with chemical compounds

• Tyrosine phosphorylation of the a kinase anchoring protein 3 (AKAP3) and soluble adenylate cyclase are involved in the increase of human sperm motility by bicarbonate [12].

Physical interactions of AKAP3

• AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa [13].
• Immunoprecipitation experiments using COS cells cotransfected with AKAP3 and either Pde4a5 or Pde4d provide evidence that PDE4A5 but not PDE4D interacts with AKAP3 [13].

Other interactions of AKAP3

• These results suggest that AKAP3 is involved in organizing the basic structure of the fibrous sheath, whereas AKAP4 has a major role in completing fibrous sheath assembly [9].
• Finally, AKAP110 significantly potentiated G alpha 13-induced activation of PKA [4].
• Immunolocalization techniques detected both PDE4A and AKAP3 (formerly known as AKAP110) in the principal piece of bovine spermatozoa [13].

Analytical, diagnostic and therapeutic context of AKAP3

• In Cox multivariate analysis, AKAP3 mRNA expression was found to be a significant predictor of both overall and progression-free survival in patients with poorly differentiated tumors [1].
• We investigated AKAP3 mRNA expression in 20 normal ovaries and 54 ovarian cancers of different histological types, grades and stages by reverse transcription-polymerase chain reaction (RT-PCR) [1].
• Co-localization of AKAP3 and Sp17 by immunofluorescence was demonstrated along the length of the principal piece of the flagella [10].
• No quantitative or qualitative differences between patients with DFS and normal controls were detected when sperm proteins were analyzed by either silver staining or immunoblot analysis using antibodies raised against AKAP4 and AKAP3 [6].
• A human sperm-oocyte binding protein, SOB1, was purified by two dimensional gel electrophoresis and sequenced [11].

References