| First Author | Penzo M | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1843 |
| Issue | 9 | Pages | 1796-1804 |
| PubMed ID | 24747690 | Mgi Jnum | J:217042 |
| Mgi Id | MGI:5612948 | Doi | 10.1016/j.bbamcr.2014.04.011 |
| Citation | Penzo M, et al. (2014) Cell migration to CXCL12 requires simultaneous IKKalpha and IKKbeta-dependent NF-kappaB signaling. Biochim Biophys Acta 1843(9):1796-804 |
| abstractText | 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 IKKbeta and IKKalpha-dependent NF-kappaB activation. IKKbeta-mediated activation maintains sufficient expression of HMGB1's receptor RAGE, while IKKalpha-dependent NF-kappaB activation ensures continuous production of CXCL12, which complexes with HMGB1 to engage CXCR4. Here using fibroblasts and primary mature macrophages, we show that IKKbeta and IKKalpha are simultaneously essential for cell migration in response to CXCL12 alone. Non-canonical NF-kappaB pathway subunits RelB and p52 are also both essential for cell migration towards CXCL12, suggesting that IKKalpha is required to drive non-canonical NF-kappaB signaling. Flow cytometric analyses of CXCR4 expression show that IKKbeta, but not IKKalpha, is required to maintain a critical threshold level of this CXCL12 receptor. Time-lapse video microscopy experiments in primary MEFs reveal that IKKalpha 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 IKKalpha-dependent p52 nuclear translocation and IKKalpha-dependent expression of the CXCL12 gene. On the basis of our collective results we posit that IKKalpha is needed to maintain the basal expression of a critical protein co-factor required for cell migration to CXCL12. |
