IQGAP1 promotes CXCR4 chemokine receptor function and trafficking via EEA-1+ endosomes

Bamidele, Adebowale O.; Kremer, Kimberly N.; Hirsova, Petra; Clift, Ian C.; Gores, Gregory J.; Billadeau, Daniel D.; Hedin, Karen E.

doi:10.1083/jcb.201411045

Cited by 18 publications

(14 citation statements)

References 74 publications

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“…IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) is a ubiquitously expressed protein, belonging to the scaffolin-family, and has emerged as a critical regulator of several signalling pathways in a variety of cell types, including immune cells, where it plays important roles for cytoskeleton-mediated processes [ 22 ]. IQGAP1 has shown to be instrumental for leukocyte chemotaxis and natural killer (NK)-cell cytotoxicity [ 23 , 24 ]. Higher IQGAP1 expression, as observed from MS risk loci, would lead to aberrant leukocyte cell migration and NK cell activity, and could thereby contribute to MS disease.…”

Section: Discussionmentioning

confidence: 99%

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

et al. 2016

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BackgroundMultiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown.ResultsConsistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele.ConclusionsOur data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0367-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

et al. 2016

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“…45 CXCR4 activity is indeed regulated by endocytosis and recycling. 46,47 Furthermore, CXCR4 recycling is dependent on Rho in human T cells. 48 Although the mechanisms for regulating CXCR4 activity remain a focus of active investigations 49 and experimental determination of CXCR4 activation state relies on indirect outcomes, our data suggest that the increased surface expression of CXCR4 reflects the loss of endocytosis, potentially leading to less active CXCR4 recycling toward the cell pole during chemotaxis and to loss of endosome-based signaling.…”

Section: Dnm Activity Regulates Actin Polymerization Rhoa Activationmentioning

confidence: 99%

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Suraneni¹,

Corey

Hession

et al. 2018

Blood Advances

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Megakaryocyte (MK) migration from the bone marrow periosteal niche toward the vascular niche is a prerequisite for proplatelet extension and release into the circulation. The mechanism for this highly coordinated process is poorly understood. Here we show that dynasore (DNSR), a small-molecule inhibitor of dynamins (DNMs), or short hairpin RNA knockdown of DNM2 and DNM3 impairs directional migration in a human MK cell line or MKs derived from cultured CD34+ cells. Because cell migration requires actin cytoskeletal rearrangements, we measured actin polymerization and the activity of cytoskeleton regulator RhoA and found them to be decreased after inhibition of DNM2 and DNM3. Because SDF-1α is important for hematopoiesis, we studied the expression of its receptor CXCR4 in DNSR-treated cells. CXCR4 expression on the cell surface was increased, at least partially because of slower endocytosis and internalization after SDF-1α treatment. Combined inhibition of DNM2 and DNM3 or forced expression of dominant-negative Dnm2-K44A or GTPase-defective DNM3 diminished β1 integrin (ITGB1) activity. DNSR-treated MKs showed an abnormally clustered staining pattern of Rab11, a marker of recycling endosomes. This suggests decreased recruitment of the recycling pathway in DNSR-treated cells. Altogether, we show that the GTPase activity of DNMs, which governs endocytosis and regulates cell receptor trafficking, exerts control on MK migration toward SDF-1α gradients, such as those originating from the vascular niche. DNMs play a critical role in MKs by triggering membrane-cytoskeleton rearrangements downstream of CXCR4 and integrins.

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“…Supporting such a mechanism, studies have documented iron-independent contributions of FTH1 to internalization of the chemokine receptor CXCR4 (refs. [55][56][57] ) and to cell surface delivery of class I MHC 58 ; both these activities depend on microtubule scaffolding [59][60][61] . However, our results do not rule out microtubule-independent influences of ferritin on EpoR transport, and Golgi vesicle release may occur even with organelle dispersion.…”

Section: Discussionmentioning

confidence: 99%

Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia

et al. 2021

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Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.

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IQGAP1 promotes CXCR4 chemokine receptor function and trafficking via EEA-1+ endosomes

Abstract: IQGAP1 mediates CXCR4 cell surface expression and signaling by regulating EEA-1+ endosome interactions with microtubules during CXCR4 trafficking and recycling.

Cited by 18 publications

References 74 publications

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia

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