PPP1R14A explained

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 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.^{[4] [3]} In prostate cancer, CPI-17 expressions are reported to be associated with GWAS risk SNP rs7247241 T allele and increase cell proliferation. ^[5]

Further reading

• Eto M, Ohmori T, Suzuki M, Furuya K, Morita F . 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 . December 1995 . 8720121 . 10.1093/oxfordjournals.jbchem.a124993 . free .
• Eto M, Senba S, Morita F, Yazawa M . 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 . June 1997 . 9237662 . 10.1016/S0014-5793(97)00657-1 . 83782622 . free .
• Koyama M, Ito M, Feng J, Seko T, Shiraki K, Takase K, Hartshorne DJ, Nakano T . 6 . Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase . FEBS Letters . 475 . 3 . 197–200 . June 2000 . 10869555 . 10.1016/S0014-5793(00)01654-9 . 24077777 . free .
• Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, Takase K, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T . 6 . Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N . Biochemical and Biophysical Research Communications . 274 . 3 . 825–830 . August 2000 . 10924361 . 10.1006/bbrc.2000.3225 .
• Li Z, Yu L, Zhang Y, Gao J, Zhang P, Wan B, Chen C, Zhao S . 6 . 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 . 2002 . 11931393 . 10.1023/A:1017998029053 . 37230257 .
• Dubois T, Howell S, Zemlickova E, Aitken A . Identification of casein kinase Ialpha interacting protein partners . FEBS Letters . 517 . 1–3 . 167–171 . April 2002 . 12062430 . 10.1016/S0014-5793(02)02614-5 . 84792445 . free .
• Liu QR, Zhang PW, Lin Z, Li QF, Woods AS, Troncoso J, Uhl GR . 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 . January 2004 . 12974676 . 1223837 . 10.1042/BJ20030128 .
• Eto M, Kitazawa T, Brautigan DL . 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 . June 2004 . 15184667 . 428442 . 10.1073/pnas.0307812101 . free . 2004PNAS..101.8888E .
• Zemlickova E, Johannes FJ, Aitken A, Dubois T . Association of CPI-17 with protein kinase C and casein kinase I . Biochemical and Biophysical Research Communications . 316 . 1 . 39–47 . March 2004 . 15003508 . 10.1016/j.bbrc.2004.02.014 .
• Kolosova IA, Ma SF, Adyshev DM, Wang P, Ohba M, Natarajan V, Garcia JG, Verin AD . 6 . Role of CPI-17 in the regulation of endothelial cytoskeleton . American Journal of Physiology. Lung Cellular and Molecular Physiology . 287 . 5 . L970–L980 . November 2004 . 15234908 . 10.1152/ajplung.00398.2003 .
• Jin H, Sperka T, Herrlich P, Morrison H . Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase . Nature . 442 . 7102 . 576–579 . August 2006 . 16885985 . 10.1038/nature04856 . free . 2006Natur.442..576J .
• Morin C, Sirois M, Echave V, Gomes MM, Rousseau E . 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 . May 2007 . 17237191 . 10.1165/rcmb.2006-0281OC .
• Lartey J, Smith M, Pawade J, Strachan B, Mellor H, López Bernal A . 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 . June 2007 . 17301291 . 10.1095/biolreprod.106.058982 . free .
• Eto M, Kitazawa T, Matsuzawa F, Aikawa S, Kirkbride JA, Isozumi N, Nishimura Y, Brautigan DL, Ohki SY . 6 . Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor . Structure . 15 . 12 . 1591–1602 . December 2007 . 18073109 . 2217667 . 10.1016/j.str.2007.10.014 .
• Dimopoulos GJ, Semba S, Kitazawa K, Eto M, Kitazawa T . Ca2+-dependent rapid Ca2+ sensitization of contraction in arterial smooth muscle . Circulation Research . 100 . 1 . 121–129 . January 2007 . 17158339 . 2212616 . 10.1161/01.RES.0000253902.90489.df .
• Kim JI, Young GD, Jin L, Somlyo AV, Eto M . Expression of CPI-17 in smooth muscle during embryonic development and in neointimal lesion formation . Histochemistry and Cell Biology . 132 . 2 . 191–198 . August 2009 . 19437030 . 2878480 . 10.1007/s00418-009-0604-2 .
• Kitazawa T, Semba S, Huh YH, Kitazawa K, Eto M . Nitric oxide-induced biphasic mechanism of vascular relaxation via dephosphorylation of CPI-17 and MYPT1 . The Journal of Physiology . 587 . Pt 14 . 3587–3603 . July 2009 . 19470783 . 2742283 . 10.1113/jphysiol.2009.172189 .

Notes and References

1. Eto M, Ohmori T, Suzuki M, Furuya K, Morita F . 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 . December 1995 . 8720121 . 10.1093/oxfordjournals.jbchem.a124993 . free .
2. Yamawaki K, Ito M, Machida H, Moriki N, Okamoto R, Isaka N, Shimpo H, Kohda A, Okumura K, Hartshorne DJ, Nakano T . 6 . Identification of human CPI-17, an inhibitory phosphoprotein for myosin phosphatase . Biochemical and Biophysical Research Communications . 285 . 4 . 1040–1045 . July 2001 . 11467857 . 10.1006/bbrc.2001.5290 .
3. Web site: Entrez Gene: PPP1R14A protein phosphatase 1, regulatory (inhibitor) subunit 14A.
4. Eto M . Regulation of cellular protein phosphatase-1 (PP1) by phosphorylation of the CPI-17 family, C-kinase-activated PP1 inhibitors . The Journal of Biological Chemistry . 284 . 51 . 35273–35277 . December 2009 . 19846560 . 2790955 . 10.1074/jbc.R109.059972 . free .
5. Tian Y, Soupir A, Liu Q, Wu L, Huang CC, Park JY, Wang L . Novel role of prostate cancer risk variant rs7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation . Human Molecular Genetics . November 2021 . 31 . 10 . 1610–1621 . 34849858 . 10.1093/hmg/ddab347 . 9122641 .