{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNHERF4, also known as IKEPP, has emerged as a key PDZ domain scaffold protein in the regulation of cellular signaling in intestinal epithelia. In studies focused on gastrointestinal function, IKEPP was shown to associate with the COOH terminus of the guanylyl cyclase C (GCC) receptor, where its binding attenuated the activation of GCC by bacterial heat-stable enterotoxins. This effect indicates that NHERF4 plays a regulatory role in modulating receptor catalytic activity, a finding that has important implications for understanding the mechanisms underlying secretory diarrhea."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "Dissecting its role in epithelial transport, NHERF4 has been demonstrated to interact directly with key transporters. In intestinal brush border studies, NHERF4 bound to the F2 region of NHE3, where its expression was associated with enhanced NHE3 activity and increased plasma membrane localization upon elevation of intracellular Ca²⁺. In another related study, the direct interaction of NHERF4 with SLC26A3 via its third PDZ domain was found to induce rapid internalization of SLC26A3 from the plasma membrane, leading to a decrease in anion exchange activity. These findings jointly suggest that NHERF4 critically modulates transporter function and composition, thereby regulating luminal fluidity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "Expanding its functional repertoire beyond the gastrointestinal tract, NHERF4 interacts with the prostacyclin IP receptor in vascular endothelial cells. Here, binding via its PDZ domains facilitates a dynamic association that is enhanced by receptor agonist-induced, protein kinase-mediated phosphorylation, ultimately promoting the receptor’s functional expression and cAMP generation. These interactions support effective endothelial cell migration and angiogenesis, highlighting NHERF4’s importance in vascular repair and hemostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Robert O Scott, William R Thelin, Sharon L Milgram "}, {"type": "b", "children": [{"type": "t", "text": "A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M202434200"}], "href": "https://doi.org/10.1074/jbc.M202434200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11950846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11950846"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nicholas C Zachos, Caleb Hodson, Olga Kovbasnjuk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated intracellular calcium stimulates NHE3 activity by an IKEPP (NHERF4) dependent mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000185553"}], "href": "https://doi.org/10.1159/000185553"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19088451"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19088451"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ji Hyun Lee, Joo Hyun Nam, Joonhee Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of SLC26A3 activity by NHERF4 PDZ-mediated interaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2012.05.010"}], "href": "https://doi.org/10.1016/j.cellsig.2012.05.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22627094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22627094"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Helen M Reid, Elizebeth C Turner, Eamon P Mulvaney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of the human prostacyclin receptor and the NHERF4 family member intestinal and kidney enriched PDZ protein (IKEPP)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2012.07.015"}], "href": "https://doi.org/10.1016/j.bbamcr.2012.07.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22884631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22884631"}]}]}]}