title: IQGAP1 promotes CXCR4 chemokine receptor function and trafficking via EEA-1+ endosomes.
abstract: IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a cytoskeleton-interacting scaffold protein. CXCR4 is a chemokine receptor that binds stromal cell-derived factor-1 (SDF-1; also known as CXCL12). Both IQGAP1 and CXCR4 are overexpressed in cancer cell types, yet it was unclear whether these molecules functionally interact. Here, we show that depleting IQGAP1 in Jurkat T leukemic cells reduced CXCR4 expression, disrupted trafficking of endocytosed CXCR4 via EEA-1(+) endosomes, and decreased efficiency of CXCR4 recycling. SDF-1-induced cell migration and activation of extracellular signal-regulated kinases 1 and 2 (ERK) MAPK were strongly inhibited, even when forced overexpression restored CXCR4 levels. Similar results were seen in KMBC and HEK293 cells. Exploring the mechanism, we found that SDF-1 treatment induced IQGAP1 binding to α-tubulin and localization to CXCR4-containing endosomes and that CXCR4-containing EEA-1(+) endosomes were abnormally located distal from the microtubule (MT)-organizing center (MTOC) in IQGAP1-deficient cells. Thus, IQGAP1 critically mediates CXCR4 cell surface expression and signaling, evidently by regulating EEA-1(+) endosome interactions with MTs during CXCR4 trafficking and recycling. IQGAP1 may similarly promote CXCR4 functions in other cancer cell types.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Adebowale O
authors.initials: AO
authors.lastname: Bamidele
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Kremer
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905 Neurobiology of Disease Research Program, Mayo Clinic, Rochester, MN 55905.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Clift
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905 Division of Oncology Research, Mayo Clinic, Rochester, MN 55905.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905 hedin.karen@mayo.edu.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hedin
mesh_terms: D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C101203:IQ motif containing GTPase activating protein 1; D019718:Receptors, CXCR4; D017465:Receptors, Opioid, delta; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D020703:ras GTPase-Activating Proteins