Gene Symbol: cpxA
Description: sensory histidine kinase in two-component regulatory system with CpxR
Alias: ECK3904, JW3882, ecfB, eup, rssE, ssd
Species: Escherichia coli str. K-12 substr. MG1655

Top Publications

  1. DiGiuseppe P, Silhavy T. Signal detection and target gene induction by the CpxRA two-component system. J Bacteriol. 2003;185:2432-40 pubmed
    ..b>CpxA resides in the inner membrane and has both kinase and phosphatase activities...
  2. Kohanski M, Dwyer D, Wierzbowski J, Cottarel G, Collins J. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell. 2008;135:679-90 pubmed publisher
  3. De Wulf P, Kwon O, Lin E. The CpxRA signal transduction system of Escherichia coli: growth-related autoactivation and control of unanticipated target operons. J Bacteriol. 1999;181:6772-8 pubmed
    ..The results suggest that the CpxRA system plays a core role in an extensive stress response network in which the coordination of protein turnover and energy conservation may be the unifying element. ..
  4. Raivio T, Laird M, Joly J, Silhavy T. Tethering of CpxP to the inner membrane prevents spheroplast induction of the cpx envelope stress response. Mol Microbiol. 2000;37:1186-97 pubmed
    ..through interactions between the periplasmic inhibitor molecule CpxP and the sensing domain of the histidine kinase CpxA. In this study, we show that depletion of the periplasmic contents of the cell by spheroplast formation does indeed ..
  5. Yamamoto K, Hirao K, Oshima T, Aiba H, Utsumi R, Ishihama A. Functional characterization in vitro of all two-component signal transduction systems from Escherichia coli. J Biol Chem. 2005;280:1448-56 pubmed
  6. Lee Y, DiGiuseppe P, Silhavy T, Hultgren S. P pilus assembly motif necessary for activation of the CpxRA pathway by PapE in Escherichia coli. J Bacteriol. 2004;186:4326-37 pubmed
    ..Thus, the data presented in this study argue that PapE has features inherent in its structure or during its folding that act as specific inducers of Cpx signal transduction. ..
  7. Wolfe A, Parikh N, Lima B, Zemaitaitis B. Signal integration by the two-component signal transduction response regulator CpxR. J Bacteriol. 2008;190:2314-22 pubmed publisher
    ..An important member of the CpxAR regulon is cpxP. The CpxA-dependent transcription of cpxP has been linked to stresses such as misfolded proteins and alkaline pH...
  8. De Wulf P, Lin E. Cpx two-component signal transduction in Escherichia coli: excessive CpxR-P levels underlie CpxA* phenotypes. J Bacteriol. 2000;182:1423-6 pubmed
    In Escherichia coli, the CpxA-CpxR two-component signal transduction system and the sigma(E) and sigma(32) response pathways jointly regulate gene expression in adaptation to adverse conditions...
  9. Yamamoto K, Ishihama A. Characterization of copper-inducible promoters regulated by CpxA/CpxR in Escherichia coli. Biosci Biotechnol Biochem. 2006;70:1688-95 pubmed
    The copper stimulon in Escherichia coli consists of four regulons, the CueR-, CusS/CusR-, CpxA/CpxR-, and YedV/YedW regulons. E. coli mutants defective in cpxRA showed higher sensitivity to copper than the wild type...

More Information


  1. McEwen J, Silverman P. Chromosomal mutations of Escherichia coli that alter expression of conjugative plasmid functions. Proc Natl Acad Sci U S A. 1980;77:513-7 pubmed
    ..We have designated the chromosomal genes identified by these mutations as cpxA and cpxB; the mnemonic cpx signifying conjugative plasmid expression.
  2. Dorel C, Lejeune P, Rodrigue A. The Cpx system of Escherichia coli, a strategic signaling pathway for confronting adverse conditions and for settling biofilm communities?. Res Microbiol. 2006;157:306-14 pubmed
    ..Current knowledge of the regulatory mechanisms of the CpxR response (transcriptional and post-transcriptional) and the interactions between CpxR and the other bacterial regulatory systems are presented. ..
  3. Danese P, Snyder W, Cosma C, Davis L, Silhavy T. The Cpx two-component signal transduction pathway of Escherichia coli regulates transcription of the gene specifying the stress-inducible periplasmic protease, DegP. Genes Dev. 1995;9:387-98 pubmed
    ..Gain-of-function mutations in cpxA, which specifies a two-component sensor protein, stimulate transcription from degP...
  4. Raivio T, Popkin D, Silhavy T. The Cpx envelope stress response is controlled by amplification and feedback inhibition. J Bacteriol. 1999;181:5263-72 pubmed
    ..It is comprised of the histidine kinase CpxA and the response regulator CpxR...
  5. Raivio T, Silhavy T. Transduction of envelope stress in Escherichia coli by the Cpx two-component system. J Bacteriol. 1997;179:7724-33 pubmed
    ..One of these signal transduction pathways is a two-component regulatory system comprised of the histidine kinase CpxA and the response regulator, CpxR...
  6. Cosma C, Danese P, Carlson J, Silhavy T, Snyder W. Mutational activation of the Cpx signal transduction pathway of Escherichia coli suppresses the toxicity conferred by certain envelope-associated stresses. Mol Microbiol. 1995;18:491-505 pubmed
    ..Suppressors of these toxicities map to a previously characterized gene, cpxA, that encodes the sensor kinase protein of a two-component regulatory system...
  7. Batchelor E, Walthers D, Kenney L, Goulian M. The Escherichia coli CpxA-CpxR envelope stress response system regulates expression of the porins ompF and ompC. J Bacteriol. 2005;187:5723-31 pubmed
    ..One mutant harbored an insertion in the gene encoding the histidine kinase CpxA, the sensor for a two-component signaling system that responds to envelope stress...
  8. Cuny C, Lesbats M, Dukan S. Induction of a global stress response during the first step of Escherichia coli plate growth. Appl Environ Microbiol. 2007;73:885-9 pubmed
    ..Our results indicate that in order to grow on plates, bacteria must not only adapt to new conditions but also perceive a real stress. ..
  9. Siryaporn A, Goulian M. Cross-talk suppression between the CpxA-CpxR and EnvZ-OmpR two-component systems in E. coli. Mol Microbiol. 2008;70:494-506 pubmed publisher
    ..that provide insulation against such interference, we have examined cross-talk between the histidine kinase CpxA and non-cognate response regulator OmpR in Escherichia coli...
  10. Price N, Raivio T. Characterization of the Cpx regulon in Escherichia coli strain MC4100. J Bacteriol. 2009;191:1798-815 pubmed publisher
  11. Pogliano J, Lynch A, Belin D, Lin E, Beckwith J. Regulation of Escherichia coli cell envelope proteins involved in protein folding and degradation by the Cpx two-component system. Genes Dev. 1997;11:1169-82 pubmed
    We show that the two-component signal transduction system of Escherichia coli, CpxA-CpxR, controls the expression of genes encoding cell envelope proteins involved in protein folding and degradation...
  12. Bury Moné S, Nomane Y, Reymond N, Barbet R, Jacquet E, Imbeaud S, et al. Global analysis of extracytoplasmic stress signaling in Escherichia coli. PLoS Genet. 2009;5:e1000651 pubmed publisher
    ..The extracytoplasmic stress signaling pathways in E. coli thus regulate mainly complementary functions whose discrete contributions are integrated to mount the full adaptive response. ..
  13. Fleischer R, Heermann R, Jung K, Hunke S. Purification, reconstitution, and characterization of the CpxRAP envelope stress system of Escherichia coli. J Biol Chem. 2007;282:8583-93 pubmed
    ..It consists of the membrane-anchored sensor kinase CpxA, the response regulator CpxR, and the periplasmic protein CpxP...
  14. Stock A, Robinson V, Goudreau P. Two-component signal transduction. Annu Rev Biochem. 2000;69:183-215 pubmed
    ..Thus detailed analyses of a relatively small number of representative proteins provide a foundation for understanding this large family of signaling proteins. ..
  15. Groban E, Clarke E, Salis H, Miller S, Voigt C. Kinetic buffering of cross talk between bacterial two-component sensors. J Mol Biol. 2009;390:380-93 pubmed publisher
    ..In this work, we studied the EnvZ/OmpR and CpxA/CpxR systems from Escherichia coli, which have been shown previously to exhibit slow cross talk in vitro...
  16. Silverman P. Gene cpxA is a new addition to the linkage map of Escherichia coli K-12. J Bacteriol. 1982;150:425-8 pubmed
    The cpxA gene of E. coli K-12 lies between genes glpK and tpi, closely linked to the latter at 87.8 min on the linkage map. Since no other gene has been mapped in this interval, cpxA is a new addition to the linkage map.
  17. Kefala G, Kwiatkowski W, Esquivies L, Maslennikov I, Choe S. Application of Mistic to improving the expression and membrane integration of histidine kinase receptors from Escherichia coli. J Struct Funct Genomics. 2007;8:167-72 pubmed
    ..Mistic fusion methods will likely be instrumental for high-level expression of other integral membrane proteins. ..
  18. Pogliano J, Dong J, De Wulf P, Furlong D, Boyd D, Losick R, et al. Aberrant cell division and random FtsZ ring positioning in Escherichia coli cpxA* mutants. J Bacteriol. 1998;180:3486-90 pubmed
    In Escherichia coli, certain mutations in the cpxA gene (encoding a sensor kinase of a two-component signal transduction system) randomize the location of FtsZ ring assembly and dramatically affect cell division...
  19. Danese P, Silhavy T. The sigma(E) and the Cpx signal transduction systems control the synthesis of periplasmic protein-folding enzymes in Escherichia coli. Genes Dev. 1997;11:1183-93 pubmed
    ..Similarly, the activity of the Cpx signal transduction pathway, which consists of an inner-membrane sensor (CpxA) and a cognate response regulator (CpxR), is stimulated by overproduction of the outer-membrane lipoprotein, NlpE...
  20. Weber R, Silverman P. The cpx proteins of Escherichia coli K12. Structure of the cpxA polypeptide as an inner membrane component. J Mol Biol. 1988;203:467-78 pubmed
    Gene cpxA of Escherichia coli K12 encodes the 52,000 Mr CpxA polypeptide...
  21. Mileykovskaya E, Dowhan W. The Cpx two-component signal transduction pathway is activated in Escherichia coli mutant strains lacking phosphatidylethanolamine. J Bacteriol. 1997;179:1029-34 pubmed
    The CpxA-CpxR two-component signal transduction pathway of Escherichia coli was studied in a mutant (pss-93) lacking phosphatidylethanolamine (PE)...
  22. Vogt S, Raivio T. Hfq reduces envelope stress by controlling expression of envelope-localized proteins and protein complexes in enteropathogenic Escherichia coli. Mol Microbiol. 2014;92:681-97 pubmed publisher
    ..This study shows that Hfq has a more extensive role in regulating the expression of envelope proteins and horizontally acquired virulence genes in E.?coli than previously recognized. ..
  23. Iuchi S, Furlong D, Lin E. Differentiation of arcA, arcB, and cpxA mutant phenotypes of Escherichia coli by sex pilus formation and enzyme regulation. J Bacteriol. 1989;171:2889-93 pubmed
    ..arcB anaerobically derepress the synthesis of a multitude of enzymes of aerobic function, and mutations in arcA or cpxA impair F-pilus formation...
  24. Arutyunov D, Arenson B, Manchak J, Frost L. F plasmid TraF and TraH are components of an outer membrane complex involved in conjugation. J Bacteriol. 2010;192:1730-4 pubmed publisher
    ..Mutational analysis of TraH revealed two domains that are important for its function and possible interaction with TrbI, which in turn has a role in stabilizing TraH. ..
  25. De Wulf P, Akerley B, Lin E. Presence of the Cpx system in bacteria. Microbiology. 2000;146 ( Pt 2):247-8 pubmed
  26. Nevesinjac A, Raivio T. The Cpx envelope stress response affects expression of the type IV bundle-forming pili of enteropathogenic Escherichia coli. J Bacteriol. 2005;187:672-86 pubmed
    ..The two-component regulatory system consisting of the sensor kinase CpxA and the response regulator CpxR senses and mediates adaptation to envelope insults believed to result in protein ..
  27. Morris J, Newman E. Map location of the ssd mutation in Escherichia coli K-12. J Bacteriol. 1980;143:1504-5 pubmed
    A pleiotropic mutation at the ssd locus was mapped at 86 min near rha...
  28. Albin R, Silverman P. Identification of the Escherichia coli K-12 cpxA locus as a single gene: construction and analysis of biologically-active cpxA gene fusions. Mol Gen Genet. 1984;197:272-9 pubmed
    ..fragment from the pfkA-rha interval of the Escherichia coli K-12 chromosome fully complemented a chromosomal cpxA mutation when the fragment was cloned in pBR325...
  29. Vogt S, Evans A, Guest R, Raivio T. The Cpx envelope stress response regulates and is regulated by small noncoding RNAs. J Bacteriol. 2014;196:4229-38 pubmed publisher
    ..sRNAs therefore permit the fine-tuning of Cpx pathway activity and its regulation of target genes, which could assist bacterial survival in the face of envelope stress. ..
  30. McEwen J, Silverman P. Genetic analysis of Escherichia coli K-12 chromosomal mutants defective in expression of F-plasmid functions: identification of genes cpxA and cpxB. J Bacteriol. 1980;144:60-7 pubmed
    ..Each mutant strain contained two altered genes: cpxA, located at 88 min on the E. coli K-12 genetic map, and cpxB, located at 41 min...
  31. Tschauner K, Hörnschemeyer P, Müller V, Hunke S. Dynamic interaction between the CpxA sensor kinase and the periplasmic accessory protein CpxP mediates signal recognition in E. coli. PLoS ONE. 2014;9:e107383 pubmed publisher
    ..Here, we analyzed the interaction between the periplasmic accessory protein CpxP and the sensor kinase CpxA in Escherichia coli in dependency of three specific stimuli...
  32. Shimohata N, Chiba S, Saikawa N, Ito K, Akiyama Y. The Cpx stress response system of Escherichia coli senses plasma membrane proteins and controls HtpX, a membrane protease with a cytosolic active site. Genes Cells. 2002;7:653-62 pubmed
    ..The pathway for this transmembrane signalling is mediated by the CpxR-CpxA two-component phospho-relay mechanism...
  33. Kurabayashi K, Hirakawa Y, Tanimoto K, Tomita H, Hirakawa H. Role of the CpxAR two-component signal transduction system in control of fosfomycin resistance and carbon substrate uptake. J Bacteriol. 2014;196:248-56 pubmed publisher
    ..A cpxA mutant lacking its phosphatase activity results in constitutive activation of its cognate response regulator, CpxR, ..
  34. Delhaye A, Collet J, Laloux G. Fine-Tuning of the Cpx Envelope Stress Response Is Required for Cell Wall Homeostasis in Escherichia coli. MBio. 2016;7:e00047-16 pubmed publisher
    ..Thus, by contributing to PG homeostasis, the Cpx system lies at the crossroads between key processes of bacterial life, including cell shape, growth, division, and antibiotic resistance. ..
  35. Keller R, Hunke S. Misfolded maltose binding protein MalE219 induces the CpxRA envelope stress response by stimulating phosphoryl transfer from CpxA to CpxR. Res Microbiol. 2009;160:396-400 pubmed publisher
    ..Surprisingly, autokinase and phosphatase activities of the reconstituted CpxA-6His protein remained unaffected, whereas phosphotransfer to CpxR became activated by MalE219...
  36. Albin R, Silverman P. Physical and genetic structure of the glpK-cpxA interval of the Escherichia coli K-12 chromosome. Mol Gen Genet. 1984;197:261-71 pubmed
    Mutations at the cpxA locus of Escherichia coli K-12 affect cellular processes that are not otherwise related. We have now determined the physical and genetic structure of the E. coli chromosome in the region of cpxA (87.5 min)...
  37. Weatherspoon Griffin N, Yang D, Kong W, Hua Z, Shi Y. The CpxR/CpxA two-component regulatory system up-regulates the multidrug resistance cascade to facilitate Escherichia coli resistance to a model antimicrobial peptide. J Biol Chem. 2014;289:32571-82 pubmed publisher
    ..of 115 strains from the Keio Collection, each of which contained a deletion at a demonstrated or predicted CpxR/CpxA-dependent locus, were tested for protamine susceptibility...
  38. Keller R, Ariöz C, Hansmeier N, Stenberg Bruzell F, Burstedt M, Vikström D, et al. The Escherichia coli Envelope Stress Sensor CpxA Responds to Changes in Lipid Bilayer Properties. Biochemistry. 2015;54:3670-6 pubmed publisher
    ..However, it is not known whether CpxA directly senses changes in the lipid bilayer or the presence of misfolded proteins due to the lack of PE in their ..
  39. Silverman P, Tran L, Harris R, Gaudin H. Accumulation of the F plasmid TraJ protein in cpx mutants of Escherichia coli. J Bacteriol. 1993;175:921-5 pubmed
    ..with normal TraJ levels, traY expression and donor-related functions were reduced in cells carrying any of four cpxA mutations...
  40. Thorbjarnardottir S, Magnúsdóttir R, Eggertsson G. Mutations determining generalized resistance to aminoglycoside antibiotics in Escherichia coli. Mol Gen Genet. 1978;161:89-98 pubmed
    ..72), close to strA (rpsL), and a locus at min. 86.5 previously discovered by Plate (1976) that we have designated ecfB. The unc and ecfB mutations are associated with defects in energy metabolism, while mutations at kanA may be in the ..
  41. Ma Q, Wood T. OmpA influences Escherichia coli biofilm formation by repressing cellulose production through the CpxRA two-component system. Environ Microbiol. 2009;11:2735-46 pubmed publisher
    ..b>CpxA phosphorylates CpxR and results in reduced csgD expression...
  42. Rainwater S, Silverman P. The Cpx proteins of Escherichia coli K-12: evidence that cpxA, ecfB, ssd, and eup mutations all identify the same gene. J Bacteriol. 1990;172:2456-61 pubmed
    An existing cpxA(Ts) mutant was resistant to amikacin at levels that inhibited completely the growth of a cpxA+ and a cpxA deletion strain and failed to grow as efficiently on exogenous proline...
  43. Macritchie D, Ward J, Nevesinjac A, Raivio T. Activation of the Cpx envelope stress response down-regulates expression of several locus of enterocyte effacement-encoded genes in enteropathogenic Escherichia coli. Infect Immun. 2008;76:1465-75 pubmed publisher
    ..Coupled with recent findings, our results suggest that Cpx-mediated down regulation of virulence is a conserved theme in a number of bacterial pathogens. ..
  44. Ogasawara H, Teramoto J, Hirao K, Yamamoto K, Ishihama A, Utsumi R. Negative regulation of DNA repair gene (ung) expression by the CpxR/CpxA two-component system in Escherichia coli K-12 and induction of mutations by increased expression of CpxR. J Bacteriol. 2004;186:8317-25 pubmed
    ..Based on the accumulated results, we conclude that ung gene expression is negatively regulated by the two-component system of CpxR/CpxA signal transduction.
  45. Appleman J, Chen L, Stewart V. Probing conservation of HAMP linker structure and signal transduction mechanism through analysis of hybrid sensor kinases. J Bacteriol. 2003;185:4872-82 pubmed
    ..sensor kinases NarX and NarQ (which respond to ligand by increasing kinase activity) and the sensor kinase CpxA (which responds to ligand by decreasing kinase activity)...
  46. Dorel C, Vidal O, Prigent Combaret C, Vallet I, Lejeune P. Involvement of the Cpx signal transduction pathway of E. coli in biofilm formation. FEMS Microbiol Lett. 1999;178:169-75 pubmed
    In a genetic screening directed to identify genes involved in biofilm formation, mutations in the cpxA gene were found to reduce biofilm formation by affecting microbial adherence to solid surfaces...
  47. Silverman P, Nat K, McEwen J, Birchman R. Selection of Escherichia coli K-12 chromosomal mutants that prevent expression of F-plasmid functions. J Bacteriol. 1980;143:1519-23 pubmed
    ..At least six of these were also deficient as deoxyribonucleic acid donors. More than half of the mutants appear to be altered in peviously undetected chromosomal genes required for the expression of F-related cellular functions. ..
  48. Siryaporn A, Perchuk B, Laub M, Goulian M. Evolving a robust signal transduction pathway from weak cross-talk. Mol Syst Biol. 2010;6:452 pubmed publisher
    ..The SK, CpxA, is bifunctional, with both kinase and phosphatase activities for its partner RR...
  49. Plasterk R, van de Putte P. The invertible P-DNA segment in the chromosome of Escherichia coli. EMBO J. 1985;4:237-42 pubmed
    ..This cross-over site is contained within a short palindromic sequence (AAACC AA GGTTT) which is more or less conserved in the recombination sites of all related DNA invertases. ..
  50. Mechaly A, Soto Diaz S, Sassoon N, Buschiazzo A, Betton J, Alzari P. Structural Coupling between Autokinase and Phosphotransferase Reactions in a Bacterial Histidine Kinase. Structure. 2017;25:939-944.e3 pubmed publisher
    ..Here, we report X-ray structures of the prototypical HK CpxA trapped as a hemi-phosphorylated dimer, and of the receiver domain from the RR partner, CpxR...
  51. Gerken H, Charlson E, Cicirelli E, Kenney L, Misra R. MzrA: a novel modulator of the EnvZ/OmpR two-component regulon. Mol Microbiol. 2009;72:1408-22 pubmed publisher
    ..determined that MzrA specifically interacts with EnvZ but not with OmpR or the related membrane sensor kinase, CpxA. This and additional genetic and biochemical evidence suggest that the interaction of MzrA with EnvZ would either ..
  52. Lau Wong I, Locke T, Ellison M, Raivio T, Frost L. Activation of the Cpx regulon destabilizes the F plasmid transfer activator, TraJ, via the HslVU protease in Escherichia coli. Mol Microbiol. 2008;67:516-27 pubmed
    ..Thus, the CpxAR stress response indirectly controls the synthesis of the F mating apparatus, a complex transenvelope type IV secretion system, by degrading TraJ. ..
  53. Keller R, Havemann J, Hunke S. Different regulatory regions are located on the sensor domain of CpxA to fine-tune signal transduction. Res Microbiol. 2011;162:405-9 pubmed publisher
    ..Here we investigated the impact of the periplasmic sensor domain of CpxA on signalling by mutational analysis in vitro...
  54. Plate C, Seely S, Laffler T. Evidence for a protonmotive force related regulatory system in Escherichia coli and its effects on lactose transport. Biochemistry. 1986;25:6127-32 pubmed
    Strains of Escherichia coli with mutations in the eup (energy-uncoupled phenotype) locus do not grow on nonfermentable carbon sources, have reduced growth yields on limiting glucose, are insensitive to colicins A and K, exhibit ..
  55. Martinez M, Duclert Savatier N, Betton J, Alzari P, Nilges M, Malliavin T. Modification in hydrophobic packing of HAMP domain induces a destabilization of the auto-phosphorylation site in the histidine kinase CpxA. Biopolymers. 2016;105:670-82 pubmed publisher
    ..Recently, X-ray crystallographic structures of the cytoplasmic region of the Escherichia coli histidine kinase CpxA were determined and a phosphotransferase-defective mutant, M228V, located in HAMP, was identified...
  56. Dong J, Iuchi S, Kwan H, Lu Z, Lin E. The deduced amino-acid sequence of the cloned cpxR gene suggests the protein is the cognate regulator for the membrane sensor, CpxA, in a two-component signal transduction system of Escherichia coli. Gene. 1993;136:227-30 pubmed
    The cpxA gene of Escherichia coli K-12 encodes a membrane-associated sensor element of a two-component signal transduction system in bacteria. The cognate regulator element, however, has not yet been definitively identified. A 2...
  57. Albin R, Weber R, Silverman P. The Cpx proteins of Escherichia coli K12. Immunologic detection of the chromosomal cpxA gene product. J Biol Chem. 1986;261:4698-705 pubmed
    Previous studies described lacZ'- and cat'-'cpxA fusion genes whose expression restored to normal all the phenotypic defects associated with cpxA mutations (Albin, R., and Silverman, P. M. (1984) Mol. Gen. Genet. 197, 272-279)...