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Loss\u2010of\u2010function mutations in\n                      <jats:italic>NHE6<\/jats:italic>\n                      cause Christianson Syndrome, an X\u2010linked neurodevelopmental and neurodegenerative disorder; however, the underlying molecular and cellular mechanisms remain unclear. Here, we describe a new role for NHE6 as a scaffolding platform for recruiting and delivering signaling molecules to the plasma membrane.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The yeast two\u2010hybrid system was used to screen a human brain cDNA library for proteins that bind to the cytoplasmic C\u2010terminus of NHE6.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Cyclin\u2010dependent kinase 5 (CDK5) was identified as a putative interacting partner. CDK5 is widely expressed and phosphorylates diverse proteins involved in vital processes, including receptor signaling, cytoskeletal organization, endocytosis, exocytosis, and apoptosis. Formation of a NHE6\/CDK5 complex was confirmed by biochemical assays and microscopy using Chinese hamster ovary AP\u20101 and human neuroblastoma SH\u2010SY5Y cells. CDK5, in a complex with its activator subunit p35\/CDK5R1, did not directly phosphorylate or regulate the membrane trafficking of NHE6. By contrast, NHE6 expression enhanced the localization of CDK5 and p35 to endosomal\u2010 and plasmalemmal\u2010enriched membrane fractions and elevated cell surface accumulation of the CDK5\u2010regulated transient receptor potential V1 (TRPV1) cation channel.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data indicate that NHE6, aside from its main pH\u2010regulatory function, can act concomitantly as a scaffold for recruitment of CDK5\/p35 to endosomes and the plasma membrane where the kinase is now primed to activate neighboring effectors important for cell function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70230","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:49:25Z","timestamp":1777445365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Recycling Endosomal (Na\n                    <sup>+<\/sup>\n                    , K\n                    <sup>+<\/sup>\n                    )\/H\n                    <sup>+<\/sup>\n                    Exchanger\n                    <scp>NHE<\/scp>\n                    6\/\n                    <scp>SLC<\/scp>\n                    9\n                    <scp>A<\/scp>\n                    6 Facilitates Signal Transduction by Shuttling Cyclin\u2010Dependent Kinase 5 to the Plasma Membrane"],"prefix":"10.1111","volume":"242","author":[{"given":"Rebecca","family":"Flessner","sequence":"first","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Ilie","sequence":"additional","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9o","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Boucher","sequence":"additional","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Anne","family":"McKinney","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8896-5306","authenticated-orcid":false,"given":"Reza","family":"Sharif\u2010Naeini","sequence":"additional","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7371-175X","authenticated-orcid":false,"given":"John","family":"Orlowski","sequence":"additional","affiliation":[{"name":"Department of Physiology McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.36.10.759"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2024-109973"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003522"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168-9525(94)90169-4"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/341123"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12041-021-01314-1"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1675-5"},{"issue":"2","key":"e_1_2_12_9_1","first-page":"98","article-title":"Complex Neurological Phenotype in Female Carriers of NHE6 Mutations","volume":"5","author":"Pescosolido M. 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