5n23

Structural highlights

Function

KAPCA_HUMAN Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

References

1. ↑ Ahmmed GU, Mehta D, Vogel S, Holinstat M, Paria BC, Tiruppathi C, Malik AB. Protein kinase Calpha phosphorylates the TRPC1 channel and regulates store-operated Ca2+ entry in endothelial cells. J Biol Chem. 2004 May 14;279(20):20941-9. Epub 2004 Mar 10. PMID:15016832 doi:10.1074/jbc.M313975200
2. ↑ Guan H, Hou S, Ricciardi RP. DNA binding of repressor nuclear factor-kappaB p50/p50 depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit. J Biol Chem. 2005 Mar 18;280(11):9957-62. Epub 2005 Jan 7. PMID:15642694 doi:10.1074/jbc.M412180200
3. ↑ D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem. 2005 Jul 15;280(28):26233-40. Epub 2005 May 19. PMID:15905176 doi:10.1074/jbc.M502003200
4. ↑ Zhang F, Hu Y, Huang P, Toleman CA, Paterson AJ, Kudlow JE. Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. J Biol Chem. 2007 Aug 3;282(31):22460-71. Epub 2007 Jun 12. PMID:17565987 doi:10.1074/jbc.M702439200
5. ↑ Xiao B, Tian X, Xie W, Jones PP, Cai S, Wang X, Jiang D, Kong H, Zhang L, Chen K, Walsh MP, Cheng H, Chen SR. Functional consequence of protein kinase A-dependent phosphorylation of the cardiac ryanodine receptor: sensitization of store overload-induced Ca2+ release. J Biol Chem. 2007 Oct 12;282(41):30256-64. Epub 2007 Aug 10. PMID:17693412 doi:10.1074/jbc.M703510200
6. ↑ Xu H, Washington S, Verderame MF, Manni A. Activation of protein kinase A (PKA) signaling mitigates the antiproliferative and antiinvasive effects of alpha-difluoromethylornithine in breast cancer cells. Breast Cancer Res Treat. 2008 Jan;107(1):63-70. Epub 2007 Feb 27. PMID:17333334 doi:10.1007/s10549-007-9536-5
7. ↑ Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Lohmann SM, Walter U. Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex. J Biol Chem. 2010 Jun 11;285(24):18352-63. doi: 10.1074/jbc.M109.077602. Epub, 2010 Mar 31. PMID:20356841 doi:10.1074/jbc.M109.077602
8. ↑ Wang W, Zhang X, Zheng J, Yang J. High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signal-regulated kinase pathway. Mol Cell Biochem. 2010 May;338(1-2):115-22. doi: 10.1007/s11010-009-0344-6. Epub , 2009 Dec 1. PMID:19949837 doi:10.1007/s11010-009-0344-6
9. ↑ Ermisch M, Firla B, Steinhilber D. Protein kinase A activates and phosphorylates RORalpha4 in vitro and takes part in RORalpha activation by CaMK-IV. Biochem Biophys Res Commun. 2011 May 13;408(3):442-6. doi:, 10.1016/j.bbrc.2011.04.046. Epub 2011 Apr 13. PMID:21514275 doi:10.1016/j.bbrc.2011.04.046
10. ↑ Vetter MM, Zenn HM, Mendez E, van den Boom H, Herberg FW, Skalhegg BS. The testis-specific Calpha2 subunit of PKA is kinetically indistinguishable from the common Calpha1 subunit of PKA. BMC Biochem. 2011 Aug 3;12:40. doi: 10.1186/1471-2091-12-40. PMID:21812984 doi:10.1186/1471-2091-12-40
11. ↑ Lignitto L, Carlucci A, Sepe M, Stefan E, Cuomo O, Nistico R, Scorziello A, Savoia C, Garbi C, Annunziato L, Feliciello A. Control of PKA stability and signalling by the RING ligase praja2. Nat Cell Biol. 2011 Apr;13(4):412-22. doi: 10.1038/ncb2209. Epub 2011 Mar 20. PMID:21423175 doi:10.1038/ncb2209