Alternative splicing regulates the subcellular localization of A-kinase anchoring protein 18 isoforms

被引:73
作者
Trotter, KW
Fraser, IDC
Scott, GK
Stutts, MJ
Scott, JD
Milgram, SL
机构
[1] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA
[2] Oregon Hlth Sci Univ, Vollum Inst, Howard Hughes Med Inst, Portland, OR 97201 USA
[3] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA
基金
英国惠康基金;
关键词
protein kinase A; AKAP; epithelia; targeting; green fluorescent protein;
D O I
10.1083/jcb.147.7.1481
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The cAMP-dependent protein kinase (PKA) is localized to specific subcellular compartments by association with A-kinase anchoring proteins (AKAPs), AKAPs are a family of functionally related proteins that bind the regulatory (R) subunit of PKA with high affinity and target the kinase to specific subcellular organelles. Recently, AKAP18, a low molecular weight plasma membrane AKAP that facilitates PKA-mediated phosphorylation of the L-type Ca2+ channel, was cloned. We now report the cloning of two additional isoforms of AKAP18, which we have designated AKAP18 beta and AKAP18 gamma, that arise from alternative mRNA splicing. The AKAP18 isoforms share a common R subunit binding site, but have distinct targeting domains. The original AKAP18 (renamed AKAP18 alpha) and AKAP18 beta target the plasma membrane when expressed in HEK-293 cells, while AKAP18 gamma is cytosolic. When expressed in epithelial cells, AKAP18 alpha is targeted to lateral membranes, whereas AKAP18 beta is accumulated at the apical membrane. A 23-amino acid insert, following the plasma membrane targeting domain, facilitates the association of AKAP18 beta with the apical membrane. The data suggest that AKAP18 isoforms are differentially targeted to modulate distinct intracellular signaling events. Furthermore, the data suggest that plasma membrane AKAPs may be targeted to subdomains of the cell surface, adding additional specificity in intracellular signaling.
引用
收藏
页码:1481 / 1492
页数:12
相关论文
共 58 条
  • [11] AKAPs: from structure to function
    Colledge, M
    Scott, JD
    [J]. TRENDS IN CELL BIOLOGY, 1999, 9 (06) : 216 - 221
  • [12] Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4,5-bisphosphate
    Dell'Acqua, ML
    Faux, MC
    Thorburn, J
    Thorburn, A
    Scott, JD
    [J]. EMBO JOURNAL, 1998, 17 (08) : 2246 - 2260
  • [13] Protein kinase A anchoring
    DellAcqua, ML
    Scott, JD
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (20) : 12881 - 12884
  • [14] Molecular characterization of a cDNA that encodes six isoforms of a novel murine A kinase anchor protein
    Dong, F
    Feldmesser, M
    Casadevall, A
    Rubin, CS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (11) : 6533 - 6541
  • [15] Ezrin is a cyclic AMP-dependent protein kinase anchoring protein
    Dransfield, DT
    Bradford, AJ
    Smith, J
    Martin, M
    Roy, C
    Mangeat, PH
    Goldenring, JR
    [J]. EMBO JOURNAL, 1997, 16 (01) : 35 - 43
  • [16] PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane
    Fanning, AS
    Anderson, JM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1999, 103 (06) : 767 - 772
  • [17] STRUCTURE AND FUNCTION OF CYCLIC NUCLEOTIDE-DEPENDENT PROTEIN-KINASES
    FRANCIS, SH
    CORBIN, JD
    [J]. ANNUAL REVIEW OF PHYSIOLOGY, 1994, 56 : 237 - 272
  • [18] A novel lipid-anchored A-kinase anchoring protein facilitates cAMP-responsive membrane events
    Fraser, IDC
    Tavalin, SJ
    Lester, LB
    Langeberg, LK
    Westphal, AM
    Dean, RA
    Marrion, NV
    Scott, JD
    [J]. EMBO JOURNAL, 1998, 17 (08) : 2261 - 2272
  • [19] CAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits
    Gao, TY
    Yatani, A
    DellAcqua, ML
    Sako, H
    Green, SA
    Dascal, N
    Scott, JD
    Hosey, MM
    [J]. NEURON, 1997, 19 (01) : 185 - 196
  • [20] GERACE L, 1992, Current Opinion in Cell Biology, V4, P637, DOI 10.1016/0955-0674(92)90083-O