Loss of ASP but not ROPN1 reduces mammalian ciliary motility.
Protein kinase A (PKA) signaling is targeted by interactions with A-kinase anchoring proteins (AKAPs) via a dimerization/docking domain on the regulatory (R) subunit of PKA. Four other mammalian proteins [AKAP-associated sperm protein (ASP), ropporin (ROPN1), sperm protein 17 (SP17) and calcium binding tyrosine-(Y)-phosphorylation regulated protein (CABYR)] share this highly conserved RII dimerization/docking (R2D2) domain. ASP and ROPN1 are 41% identical in sequence, interact with a variety of AKAPs in a manner similar to PKA, and are expressed in ciliated and flagellated human cells. To test the hypothesis that these proteins regulate motility, we developed mutant mouse lines lacking ASP or ROPN1. Both mutant lines produced normal numbers of cilia with intact ciliary ultrastructure. Lack of ROPN1 had no effect on ciliary motility. However, the beat frequency of cilia from mice lacking ASP is significantly slower than wild type, indicating that ASP signaling may regulate ciliary motility. This is the first demonstration of in vivo function for ASP. Similar localization of ASP in mice and humans indicates that these findings may translate to human physiology, and that these mice will be an excellent model for future studies related to the pathogenesis of human disease.
VA Medical Center, 3710 SW US Veterans' Hospital Rd., Portland, Oregon 97239, USA.
Sarah E
SE
Fiedler
Joseph H
JH
Sisson
Todd A
TA
Wyatt
Jacqueline A
JA
Pavlik
Todd M
TM
Gambling
Johnny L
JL
Carson
Daniel W
DW
Carr
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002923:Cilia / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005838:Genotype; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D015398:Signal Transduction; D013081:Sperm Motility / Q000502:physiology; D013094:Spermatozoa / Q000378:metabolism / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000172:deficiency* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C485763:Ropn1 protein, mouse; C487792:Ropn1l protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D020741:rho GTP-Binding Proteins