Alternative titles; symbols
HGNC Approved Gene Symbol: NHERF4
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:119,185,475-119,190,213 (from NCBI)
Guanylyl cyclase C (GCC, or GUCY2C; 601330) produces cGMP following the binding of either endogenous ligands or heat-stable enterotoxins secreted by E. coli and other enteric bacteria. Activation of GCC initiates a signaling cascade that leads to phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR; 602421), followed by a net efflux of ions and water into the intestinal lumen. IKEPP is a regulatory protein that associates with GCC and regulates the amount of cGMP produced following receptor stimulation (Scott et al., 2002).
Using the C-terminal extension peptide (CTEP) of GCC as bait in a yeast 2-hybrid screen, Scott et al. (2002) cloned IKEPP from an intestine cDNA library. The deduced 505-amino acid protein has a theoretical molecular mass of 54.2 kD and contains 4 peptide-binding PDZ domains. IKEPP is most closely related to PDZK1 (603831) and shares 77% sequence identity with the mouse type IIa sodium/inorganic phosphate cotransporter (SLC34A1; 182309)-associated protein. Northern blot analysis revealed expression of 2.3- and 2.5-kb IKEPP transcripts at high levels in kidney, with lower levels in intestine and colon and no expression in other tissues. mRNA Dot blot analysis of multiple gastrointestinal tissues detected IKEPP expression along the entire gastrointestinal tract, from the duodenum to the colon. Immunolocalization studies using colon carcinoma and adenocarcinoma cells showed that IKEPP preferentially accumulates in the subapical compartment and at the apical membrane. In normal human ileum and colon, IKEPP preferentially accumulated at the apical surface and was visualized in cells of the crypt and villus.
By in vitro binding assays and coimmunoprecipitations with truncation mutants of GCC, Scott et al. (2002) determined that IKEPP binds specifically to the final 4 amino acids (SYTF) of GCC. Transient transfection in COS-7 cells indicated that this interaction is not required for proper GCC targeting to the plasma membrane, but it may inhibit receptor activation and generation of cGMP in response to treatment with heat-stable enterotoxin.
Scott et al. (2002) mapped the IKEPP gene to chromosome 11q23 by genomic sequence analysis.
Scott, R. O., Thelin, W. R., Milgram, S. L. A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor. J. Biol. Chem. 277: 22934-22941, 2002. [PubMed: 11950846] [Full Text: https://doi.org/10.1074/jbc.M202434200]