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Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.

ABSTRACT: The precise signals responsible for differentiation of blood-borne monocytes into tissue macrophages are incompletely defined. "Outside-in" signaling by integrins has been implicated in modulation of gene expression that affects cellular differentiation. Herein, using differential display PCR, we have cloned an 85-kDa forkhead transcription factor (termed Mac-1-regulated forkhead [MFH] and found subsequently to be identical to Foxp1) that is downregulated in beta(2)-integrin Mac-1-clustered compared with Mac-1-nonclustered monocytic THP-1 cells. MFH/Foxp1 is expressed in untreated HL60 cells, and its expression was markedly reduced during phorbol ester-induced monocyte differentiation, but not retinoic acid-induced granulocyte differentiation. Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. This was accompanied by decreased CD11b expression, cell adhesiveness, and phagocytosis. Using electromobility shift and reporter assays, we have established that MFH/Foxp1 binds to previously uncharacterized sites within the c-fms promoter and functions as a transcriptional repressor. Deficiency of Mac-1 is associated with altered regulation of MFH/Foxp1 and monocyte maturation in vivo. Taken together, these observations suggest that Mac-1 engagement orchestrates monocyte-differentiation signals by regulating the expression of the forkhead transcription repressor MFH/Foxp1. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.

SUBMITTER: Shi C

PROVIDER: S-EPMC484980 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.

Shi Can C Zhang Xiaobin X Chen Zhiping Z Sulaiman Karina K Feinberg Mark W MW Ballantyne Christie M CM Jain Mukesh K MK Simon Daniel I DI

The Journal of clinical investigation 20040801 3

The precise signals responsible for differentiation of blood-borne monocytes into tissue macrophages are incompletely defined. "Outside-in" signaling by integrins has been implicated in modulation of gene expression that affects cellular differentiation. Herein, using differential display PCR, we have cloned an 85-kDa forkhead transcription factor (termed Mac-1-regulated forkhead [MFH] and found subsequently to be identical to Foxp1) that is downregulated in beta(2)-integrin Mac-1-clustered comp ...[more]

PMID: 15286807

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Project description:Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and β1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1α (SDF-1α) as well as decreased α5β1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of α5β1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of β1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of β1-integrin back to the plasma membrane following normal endocytosis of α5β1-integrin, suggesting that the involvement of GMFG in maintaining α5β1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting β1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased β1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited β1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of α5β1-integrin and facilitating effective β1-integrin recycling back to the plasma membrane.

Dataset Information

Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.

Publications

Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.

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