Structure, function, and regulation of human cAMP-dependent protein kinases.
A large number of hormones, neurotransmitters, and other signaling substances that bind to G-protein-coupled cell-surface receptors have their signals converge at one sole second messenger, cAMP. The question of how specificity can be maintained in a signal-transduction system in which many extracellular signals leading to a vast array of intracellular responses are all mediated through one second-messenger system has been the subject of thorough investigation and a great deal of speculation. An increasing number of cAK isozymes, consisting of homo- or heterodimers of R subunits (RIalpha, RIbeta, RIIalpha, RIIbeta) with associated catalytic subunits (C alpha, Cbeta, Cgamma), may, at least in part, explain this specificity. The various cAK isozymes display distinct biochemical properties, and the heterogeneous subunits of cAK reveal cell-specific expression and differential regulation at the level of gene transcription, mRNA stability, and protein stability in response to a wide range of hormones and other signaling substances. The existence of a number of anchoring proteins specific to either RIIalpha or RIIbeta, and which localize cAKII isozymes toward distinct substrates at defined subcellular loci, strongly supports the idea that specific functions can be assigned to the various cAK isozymes. The demonstration that selective activation of cAKI is necessary and sufficient for cAMP-mediated inhibition of T-cell proliferation, and the observation that T-cell activation is associated with redistribution and colocalization of cAKI to the TCR, is also compatible with the notion of isozyme-specific effects.
Taskén
K
K
Institute of Medical Biochemistry, University of Oslo, Norway.
Skålhegg
B S
BS
Taskén
K A
KA
Solberg
R
R
Knutsen
H K
HK
Levy
F O
FO
Sandberg
M
M
Orstavik
S
S
Larsen
T
T
Johansen
A K
AK
Vang
T
T
Schrader
H P
HP
Reinton
N T
NT
Torgersen
K M
KM
Hansson
V
V
Jahnsen
T
T
D003001:Cloning, Molecular; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation; D011487:Protein Conformation; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D014018:Tissue Distribution
D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D007527:Isoenzymes; C517834:PRKAR1A protein, human; C517766:PRKAR1B protein, human; C517819:PRKAR2A protein, human; C517837:PRKAR2B protein, human; D017868:Cyclic AMP-Dependent Protein Kinases