PPP1R14A

PPP1R14A
Identifiers
Aliases	PPP1R14A, CPI-17, CPI17, PPP1INL, protein phosphatase 1 regulatory inhibitor subunit 14A
External IDs	OMIM: 608153; MGI: 1931139; HomoloGene: 12267; GeneCards: PPP1R14A; OMA:PPP1R14A - orthologs
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7|7 B1 Start 28,988,733 bp End 28,993,226 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right coronary artery ascending aorta popliteal artery left coronary artery saphenous vein inferior ganglion of vagus nerve gastric mucosa right lung substantia nigra left uterine tube Top expressed in tunica media of zone of aorta ascending aorta umbilical cord lumbar subsegment of spinal cord right lung left lung lobe aortic valve right lung lobe anterior horn of spinal cord deep cerebellar nuclei More reference expression data BioGPS n/a
Gene ontology Molecular function protein phosphatase inhibitor activity protein serine/threonine phosphatase inhibitor activity Cellular component cytoplasm cytosol Biological process regulation of phosphorylation negative regulation of phosphoprotein phosphatase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 94274 68458 Ensembl n/a ENSMUSG00000037166 UniProt Q96A00 Q91VC7 RefSeq (mRNA) NM_033256 NM_001243947 NM_026731 RefSeq (protein) NP_001230876 NP_150281 NP_081007 Location (UCSC) n/a Chr 7: 28.99 – 28.99 Mb PubMed search
Wikidata
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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.

Function

CPI-17 is a phosphorylation-dependent inhibitor protein of smooth muscle myosin phosphatase, discovered in pig aortic homogenates. 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. In prostate cancer, CPI-17 expressions are reported to be associated with GWAS risk SNP rs7247241 T allele and increase cell proliferation.

Further reading

• Eto M, Ohmori T, Suzuki M, Furuya K, Morita F (December 1995). "A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C. Isolation from porcine aorta media and characterization". Journal of Biochemistry. 118 (6): 1104–1107. doi:10.1093/oxfordjournals.jbchem.a124993. PMID 8720121.
• Eto M, Senba S, Morita F, Yazawa M (June 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 Letters. 410 (2–3): 356–360. doi:10.1016/S0014-5793(97)00657-1. PMID 9237662. S2CID 83782622.
• Koyama M, Ito M, Feng J, Seko T, Shiraki K, Takase K, et al. (June 2000). "Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase". FEBS Letters. 475 (3): 197–200. doi:10.1016/S0014-5793(00)01654-9. PMID 10869555. S2CID 24077777.
• Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, et al. (August 2000). "Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N". Biochemical and Biophysical Research Communications. 274 (3): 825–830. doi:10.1006/bbrc.2000.3225. PMID 10924361.
• Li Z, Yu L, Zhang Y, Gao J, Zhang P, Wan B, 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". Molecular Biology Reports. 28 (2): 91–101. doi:10.1023/A:1017998029053. PMID 11931393. S2CID 37230257.
• Dubois T, Howell S, Zemlickova E, Aitken A (April 2002). "Identification of casein kinase Ialpha interacting protein partners". FEBS Letters. 517 (1–3): 167–171. doi:10.1016/S0014-5793(02)02614-5. PMID 12062430. S2CID 84792445.
• Liu QR, Zhang PW, Lin Z, Li QF, Woods AS, Troncoso J, Uhl GR (January 2004). "GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA". The Biochemical Journal. 377 (Pt 1): 171–181. doi:10.1042/BJ20030128. PMC 1223837. PMID 12974676.
• Eto M, Kitazawa T, Brautigan DL (June 2004). "Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of protein phosphatase-1 by regulatory subunits". Proceedings of the National Academy of Sciences of the United States of America. 101 (24): 8888–8893. Bibcode:2004PNAS..101.8888E. doi:10.1073/pnas.0307812101. PMC 428442. PMID 15184667.
• Zemlickova E, Johannes FJ, Aitken A, Dubois T (March 2004). "Association of CPI-17 with protein kinase C and casein kinase I". Biochemical and Biophysical Research Communications. 316 (1): 39–47. doi:10.1016/j.bbrc.2004.02.014. PMID 15003508.
• Kolosova IA, Ma SF, Adyshev DM, Wang P, Ohba M, Natarajan V, et al. (November 2004). "Role of CPI-17 in the regulation of endothelial cytoskeleton". American Journal of Physiology. Lung Cellular and Molecular Physiology. 287 (5): L970–L980. doi:10.1152/ajplung.00398.2003. PMID 15234908.
• Jin H, Sperka T, Herrlich P, Morrison H (August 2006). "Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase". Nature. 442 (7102): 576–579. Bibcode:2006Natur.442..576J. doi:10.1038/nature04856. PMID 16885985.
• Morin C, Sirois M, Echave V, Gomes MM, Rousseau E (May 2007). "Epoxyeicosatrienoic acid relaxing effects involve Ca2+-activated K+ channel activation and CPI-17 dephosphorylation in human bronchi". American Journal of Respiratory Cell and Molecular Biology. 36 (5): 633–641. doi:10.1165/rcmb.2006-0281OC. PMID 17237191.
• Lartey J, Smith M, Pawade J, Strachan B, Mellor H, López Bernal A (June 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". Biology of Reproduction. 76 (6): 971–982. doi:10.1095/biolreprod.106.058982. PMID 17301291.
• Eto M, Kitazawa T, Matsuzawa F, Aikawa S, Kirkbride JA, Isozumi N, et al. (December 2007). "Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor". Structure. 15 (12): 1591–1602. doi:10.1016/j.str.2007.10.014. PMC 2217667. PMID 18073109.
• Dimopoulos GJ, Semba S, Kitazawa K, Eto M, Kitazawa T (January 2007). "Ca2+-dependent rapid Ca2+ sensitization of contraction in arterial smooth muscle". Circulation Research. 100 (1): 121–129. doi:10.1161/01.RES.0000253902.90489.df. PMC 2212616. PMID 17158339.
• Kim JI, Young GD, Jin L, Somlyo AV, Eto M (August 2009). "Expression of CPI-17 in smooth muscle during embryonic development and in neointimal lesion formation". Histochemistry and Cell Biology. 132 (2): 191–198. doi:10.1007/s00418-009-0604-2. PMC 2878480. PMID 19437030.
• Kitazawa T, Semba S, Huh YH, Kitazawa K, Eto M (July 2009). "Nitric oxide-induced biphasic mechanism of vascular relaxation via dephosphorylation of CPI-17 and MYPT1". The Journal of Physiology. 587 (Pt 14): 3587–3603. doi:10.1113/jphysiol.2009.172189. PMC 2742283. PMID 19470783.