title: Cell migration to CXCL12 requires simultaneous IKKα and IKKβ-dependent NF-κB signaling.
abstract: CXCL12 and its unique receptor CXCR4, is critical for the homing of a variety of cell lineages during both development and tissue repair. CXCL12 is particularly important for the recruitment of hemato/lymphopoietic cells to their target organs. In conjunction with the damage-associated alarmin molecule HMGB1, CXCL12 mediates immune effector and stem/progenitor cell migration towards damaged tissues for subsequent repair. Previously, we showed that cell migration to HMGB1 simultaneously requires both IKKβ and IKKα-dependent NF-κB activation. IKKβ-mediated activation maintains sufficient expression of HMGB1's receptor RAGE, while IKKα-dependent NF-κB activation ensures continuous production of CXCL12, which complexes with HMGB1 to engage CXCR4. Here using fibroblasts and primary mature macrophages, we show that IKKβ and IKKα are simultaneously essential for cell migration in response to CXCL12 alone. Non-canonical NF-κB pathway subunits RelB and p52 are also both essential for cell migration towards CXCL12, suggesting that IKKα is required to drive non-canonical NF-κB signaling. Flow cytometric analyses of CXCR4 expression show that IKKβ, but not IKKα, is required to maintain a critical threshold level of this CXCL12 receptor. Time-lapse video microscopy experiments in primary MEFs reveal that IKKα is required both for polarization of cells towards a CXCL12 gradient and to establish a basal level of velocity towards CXCL12. In addition, CXCL12 modestly up-regulates IKKα-dependent p52 nuclear translocation and IKKα-dependent expression of the CXCL12 gene. On the basis of our collective results we posit that IKKα is needed to maintain the basal expression of a critical protein co-factor required for cell migration to CXCL12.
authors.affiliation: CRBA Laboratory and Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.|Biochemistry and Cell Biology Dept., Stony Brook University, Stony Brook, New York 11794-5215, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Penzo
authors.affiliation: Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, 11794 USA.|Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Habiel
authors.affiliation: Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, 11794 USA.|Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794, USA.
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Ramadass
authors.affiliation: Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, 11794 USA.|Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Kew
authors.affiliation: Biochemistry and Cell Biology Dept., Stony Brook University, Stony Brook, New York 11794-5215, USA.|Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, 11794 USA.|Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794, USA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Marcu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D016328:NF-kappa B; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D051996:Transcription Factor RelA; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: CXCL12; CXCR4; Cell migration; IKKα; IKKβ; NF-κB
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