PPP1R14A
Protein phosphatase 1 regulatory subunit 14A also known as CPI-17 (C-kinase potentiated Protein phosphatase-1 Inhibitor Mr = 17 kDa) is a protein that in humans is encoded by the PPP1R14A gene.[1][2][3]
Function
CPI-17 is a phosphorylation-dependent inhibitor protein of smooth muscle myosin phosphatase, discovered in pig aortic homogenetes. Phosphorylation of the Thr-38 residue converts the protein into a potent inhibitor for myosin phosphatase. A single phosphorylation of CPI-17 at Thr-38 triggers a global conformational change that causes re-alignment of four helices. Multiple kinases are identified to phosphorylate CPI-17, such as PKC, ROCK, PKN, ZIPK, ILK, and PAK. Agonist stimulation of smooth muscle enhances CPI-17 phosphorylation mainly through PKC and ROCK. Myosin phosphatase inhibition increases myosin phosphorylation and smooth muscle contraction in the absence of increased intracellular Ca2+ concentration. This phenomenon is known as Ca2+ sensitization, which occurs in response to agonist stimulation of smooth muscle. In Purkinje neuron, CPI-17 is involved in long-term synaptic depression.
There are three homologues of CPI-17:
- Phosphatase Holoenzyme Inhibitor (PHI: PPP1R14B),
- Kinase Enhanced Phosphatase Inhibitor (KEPI: PPP1R14C), and
- Gastric-Brain Phosphatase Inhibitor (GBPI: PPP1R14D).
Clinical significance
CPI-17 is up-regulated some cancer cells, and causes hyperphosphorylation of tumor suppressor merlin/NF2.[4][3]
References
- ^ Eto M, Ohmori T, Suzuki M, et al. (1996). "A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C. Isolation from porcine aorta media and characterization.". J. Biochem. 118 (6): 1104–7. doi:10.1074/jbc.R109.059972. PMID 8720121.
- ^ Yamawaki K, Ito M, Machida H, Moriki N, Okamoto R, Isaka N, Shimpo H, Kohda A, Okumura K, Hartshorne DJ, Nakano T (Jul 2001). "Identification of human CPI-17, an inhibitory phosphoprotein for myosin phosphatase". Biochem Biophys Res Commun 285 (4): 1040–5. doi:10.1006/bbrc.2001.5290. PMID 11467857.
- ^ a b "Entrez Gene: PPP1R14A protein phosphatase 1, regulatory (inhibitor) subunit 14A". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=94274.
- ^ Eto M; Ohmori, T; Suzuki, M; Furuya, K; Morita, F (2009). "Regulation of Cellular Protein Phosphatase-1 (PP1) by Phosphorylation of the CPI-17 Family, C-kinase-activated PP1 Inhibitors". J. Biol. Chem. 284 (51): 35273–7. doi:10.1074/jbc.R109.059972. PMC 2790955. PMID 8720121. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2790955.
Further reading
- Eto M, Ohmori T, Suzuki M, et al. (1996). "A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C. Isolation from porcine aorta media and characterization". J. Biochem. 118 (6): 1104–7. doi:10.1074/jbc.R109.059972. PMID 8720121.
- Eto M, Senba S, Morita F, Yazawa M (1997). "Molecular cloning of a novel phosphorylation-dependent inhibitory protein of protein phosphatase-1 (CPI17) in smooth muscle: its specific localization in smooth muscle". FEBS Lett. 410 (2–3): 356–60. doi:10.1016/S0014-5793(97)00657-1. PMID 9237662.
- Koyama M, Ito M, Feng J, et al. (2000). "Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase". FEBS Lett. 475 (3): 197–200. doi:10.1016/S0014-5793(00)01654-9. PMID 10869555.
- Hamaguchi T, Ito M, Feng J, et al. (2000). "Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N". Biochem. Biophys. Res. Commun. 274 (3): 825–30. doi:10.1006/bbrc.2000.3225. PMID 10924361.
- Li Z, Yu L, Zhang Y, et al. (2002). "Identification of human, mouse and rat PPP1R14A, protein phosphatase-1 inhibitor subunit 14A, & mapping human PPP1R14A to chromosome 19q13.13-q13.2". Mol. Biol. Rep. 28 (2): 91–101. doi:10.1023/A:1017998029053. PMID 11931393.
- Dubois T, Howell S, Zemlickova E, Aitken A (2002). "Identification of casein kinase Ialpha interacting protein partners". FEBS Lett. 517 (1–3): 167–71. doi:10.1016/S0014-5793(02)02614-5. PMID 12062430.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Liu QR, Zhang PW, Lin Z, et al. (2004). "GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA". Biochem. J. 377 (Pt 1): 171–81. doi:10.1042/BJ20030128. PMC 1223837. PMID 12974676. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1223837.
- Eto, M., Kitazawa, T., and Brautigan, D.L. (2004). "Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of protein phosphatase-1 by regulatory subunits". Proc. Natl. Acad. Sci. USA 101 (24): 8888–93. doi:10.1073/pnas.0307812101. PMC 428442. PMID 15184667. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=428442.
- Zemlickova E, Johannes FJ, Aitken A, Dubois T (2004). "Association of CPI-17 with protein kinase C and casein kinase I". Biochem. Biophys. Res. Commun. 316 (1): 39–47. doi:10.1016/j.bbrc.2004.02.014. PMID 15003508.
- Kolosova IA, Ma SF, Adyshev DM, et al. (2004). "Role of CPI-17 in the regulation of endothelial cytoskeleton". Am. J. Physiol. Lung Cell Mol. Physiol. 287 (5): L970–80. doi:10.1152/ajplung.00398.2003. PMID 15234908.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
- Jin H, Sperka T, Herrlich P, Morrison H (2006). "Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase". Nature 442 (7102): 576–9. doi:10.1038/nature04856. PMID 16885985.
- Morin C, Sirois M, Echave V, et al. (2007). "Epoxyeicosatrienoic acid relaxing effects involve Ca2+-activated K+ channel activation and CPI-17 dephosphorylation in human bronchi". Am. J. Respir. Cell Mol. Biol. 36 (5): 633–41. doi:10.1165/rcmb.2006-0281OC. PMID 17237191.
- Lartey J, Smith M, Pawade J, et al. (2007). "Up-regulation of myometrial RHO effector proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) phosphorylation in human pregnancy is associated with increased GTP-RHOA in spontaneous preterm labor". Biol. Reprod. 76 (6): 971–82. doi:10.1095/biolreprod.106.058982. PMID 17301291.
- Eto M., Kitazawa T., et al (2007). "Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor". Structure 15 (12): 1591–602. doi:10.1016/j.str.2007.10.014. PMC 2217667. PMID 18073109. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2217667.
- Dimopoulous, G. J., Semba, S., et al (2007). "Ca2+-Dependent Rapid Ca2+ Sensitization of Contraction in Arterial Smooth Muscle". Circ. Res. 100 (1): 121–29. doi:10.1161/01.RES.0000253902.90489.df. PMC 2212616. PMID 17158339. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2212616.
- Kim, J.I., Young, G.D., et al (2009). "Expression of CPI-17 in smooth muscle during embryonic development and in neointimal lesion formation". Histochem. Cell Biol. 132 (2): 191–8. doi:10.1007/s00418-009-0604-2. PMC 2878480. PMID 19437030. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2878480.
- Kitazawa, T., Semba, S., et al (2009). "Nitric oxide-induced biphasic mechanism of vascular relaxation via dephosphorylation of CPI-17 and MYPT1". J. Physiol. 587 (Pt14): 3587–603. doi:10.1113/jphysiol.2009.172189. PMC 2742283. PMID 19470783. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2742283.