Histidine kinase member of the two-component regulatory system CpxA/CpxR which responds to envelope stress response by activating expression of downstream genes including cpxP, degP, dsbA and ppiA (PubMed:7883164, PubMed:9401031, PubMed:9473036). Activates CpxR by phosphorylation; has autokinase, phosphotransferase and (in the presence of Mg(2+) and/or ATP or ADP) phosphatase activity (PubMed:9401031, PubMed:17259177, PubMed:24492262). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Involved in several diverse cellular processes, including the functioning of acetohydroxyacid synthetase I, the biosynthesis of isoleucine and valine, the TraJ protein activation activity for tra gene expression in F plasmid (PubMed:8432716), and the synthesis, translocation, or stability of cell envelope proteins (PubMed:7883164). Activates transcription of periplasmic protease degP, probably by phosphorylating the cognate response protein CpxR; overexpression of an outer membrane lipoprotein NlpE also leads to transcription of degP via CpxRA (PubMed:7883164). Required for efficient binding of stationary phase cells to hydrophobic surfaces, part of the process of biofilm formation (PubMed:11830644). ATP + protein L-histidine = ADP + protein N-phospho-L-histidine. Phosphotransfer to CpxR is stimulated by Mg(2+) and/or Mn(2+). The two-component system is activated by envelope stress such as overexpression of some (misfolded) periplasmic proteins (PubMed:7883164, PubMed:9351822). Activated by spheroplasting (which removes the periplasm) in an autoregulatory cpxA-cpxR-dependent fashion (PubMed:10972835). Cpx two-component system is induced at pH 8.0; in a degP deletion mutant induction is halved (PubMed:9473036, PubMed:16166523). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Autokinase activity reconstituted in liposomes is 50% inhibited by periplasmic accessory protein CpxP, but CpxP has no effect on phosphatase activity; autokinase stimulated by KCl, NH(4)Cl, RbCl, pH 7.5 and 8.0, inhibited by sensor kinase inhibitors tetrachlorosalicylanilid and ethodin (PubMed:17259177). The isolated cytoplasmic domain (residues 188-457) crystallizes as a homodimer, and forms dimers of dimers in solution which may be catalytically important (PubMed:24492262). Interacts with periplasmic accessory protein CpxP (PubMed:16166523, PubMed:21317318, PubMed:21239493, PubMed:25207645); interaction with CpxP is not seen in vivo when cells are grown in 0.3 M NaCl, or if the misfolded P pili protein PapE is overexpressed (PubMed:25207645). Interacts with cognate response regulator CpxR (PubMed:25207645). The periplasmic segment (residues 30-163) defines the sensory domain (PubMed:9401031). Conformational changes in the cytoplasmic HAMP domain modulate the mobility of the central alpha-helices (which bend at Ser-238 and Pro-253) that allows formation of 1 kinase-active state. Autophosphorylated (PubMed:9401031, PubMed:24492262). Maximal phosphorylation of the dimeric isolated cytoplasmic domain (residues 188-457) is about 70%, suggesting the protein may be hemiphosphorylated in vivo; probably occurs via a trans-autophosphorylation mechanism, i.e. one subunit phosphorylates the other (PubMed:24492262). Loss of the Cpx envelope stress response (PubMed:10972835). Decreased resistance to the antibiotic amnikacin (PubMed:2185221). Single cpxA and double cpxR-cpxA mutant decrease transcription of degP (PubMed:7883164). Decreased transcription of cpxP (PubMed:9473036). Hypersensitive to alkaline pH (greater than pH 8.8) (PubMed:9473036). Decreased numbers of stationary phase cells bind to hydrophobic surfaces (PubMed:11830644). Greatly increased resistance to hydroxyurea, probably due to decreased recognition of mis-folded proteins which eventually leads to decreased OH radical formation (PubMed:20005847). Truncated N-terminus.