The Fps/Fes kinase regulates leucocyte recruitment and extravasation during inflammation

Parsons, Sean A.; Mewburn, Jeffrey; Truesdell, Peter; Greer, Peter A.

doi:10.1111/j.1365-2567.2007.02670.x

Cited by 23 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also speculate that Fes-deficient macrophages will be hypersensitive to M1-polarization. We have previously shown that fes-null mice display hyperinflammatory responses to LPS (13), which were further characterized in vivo by increased leukocyte recruitment to locally inflamed tissues and increased levels of systemic TNFα (47). Cultured fes-null macrophages displayed prolonged LPS-induced activation of NFκB, increased TNFα production and reduced internalization of the TLR4 receptor complex (14).…”

Section: Discussionmentioning

confidence: 99%

Fes Tyrosine Kinase Expression in the Tumor Niche Correlates with Enhanced Tumor Growth, Angiogenesis, Circulating Tumor Cells, Metastasis, and Infiltrating Macrophages

et al. 2011

Self Cite

View full text Add to dashboard Cite

Fes is a protein tyrosine kinase with cell autonomous oncogenic activities that are well established in cell culture and animal models, but its involvement in human cancer has been unclear. Abundant expression of Fes in vascular endothelial cells and myeloid cell lineages prompted us to explore roles for Fes in the tumor microenvironment. In an orthotopic mouse model of breast cancer, we found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis, and circulating tumor cells. The tumor microenvironment in Fes-deficient mice also showed reduced vascularity and fewer macrophages. In co-culture with tumor cells, Fes-deficient macrophages also poorly promoted tumor cell invasive behavior. Taken together, our observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, in part by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages.

show abstract

Section: Discussionmentioning

confidence: 99%

Fes Tyrosine Kinase Expression in the Tumor Niche Correlates with Enhanced Tumor Growth, Angiogenesis, Circulating Tumor Cells, Metastasis, and Infiltrating Macrophages

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously, we have demonstrated a role for the group IV nonreceptor PTKs, Fer (20,21) and Fes (30,31), in leukocyte recruitment in vivo in response to local LPS injection. LPS induces recruitment through the induction of many different chemoattractants.…”

Section: Discussionmentioning

confidence: 97%

Fer Kinase Limits Neutrophil Chemotaxis toward End Target Chemoattractants

Khajah

Andonegui

Chan

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Neutrophil recruitment and directional movement toward chemotactic stimuli are important processes in innate immune responses. This study examines the role of Fer kinase in neutrophil recruitment and chemotaxis to various chemoattractants in vitro and in vivo. Mice targeted with a kinase-inactivating mutation (FerDR/DR) or wild type (WT) were studied using time-lapse intravital microscopy to examine leukocyte recruitment and chemotaxis in vivo. In response to keratinocyte-derived cytokine, no difference in leukocyte chemotaxis was observed between WT and FerDR/DR mice. However, in response to the chemotactic peptide WKYMVm, a selective agonist of the formyl peptide receptor, a 2-fold increase in leukocyte emigration was noted in FerDR/DR mice (p < 0.05). To determine whether these defects were due to Fer signaling in the endothelium or other nonhematopoietic cells, bone marrow chimeras were generated. WKYMVm-induced leukocyte recruitment in chimeric mice (WT bone marrow to FerDR/DR recipients or vice versa) was similar to WT mice, suggesting that Fer kinase signaling in both leukocytes and endothelial cells serves to limit chemotaxis. Purified FerDR/DR neutrophils demonstrated enhanced chemotaxis toward end target chemoattractants (WKYMVm and C5a) compared with WT using an under-agarose gel chemotaxis assay. These defects were not observed in response to intermediate chemoattractants (keratinocyte-derived cytokine, MIP-2, or LTB4). Increased WKYMVm-induced chemotaxis of FerDR/DR neutrophils correlated with sustained PI3K activity and reduced reliance on the p38 MAPK pathway compared with WT neutrophils. Together, these data identify Fer as a novel inhibitory kinase for neutrophil chemotaxis toward end target chemoattractants through modulation of PI3K activity.

show abstract

“…Studies of lipopolysaccharide-treated fes-null mice implicate FES in regulating cytokine production and leukocyte extravasation, which correlated with defects in TLR4 internalization in macrophages (53,54). Wei and colleagues recently showed that along with SCF, tumor cells shed ligands for TLR4, and that costimulation of KIT and TLR4 signaling in tumor-associated mast cells leads to enhanced secretion of cytokines (e.g., VEGF and IL-10) that enhance tumor progression (55).…”

Section: Discussionmentioning

confidence: 99%

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

Kwok

Everingham

Zhang

et al. 2012

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow-derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerizationdisrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosinebinding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT-and FESdependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement. Mol Cancer Res; 10(7); 881-91. Ó2012 AACR.

show abstract

The Fps/Fes kinase regulates leucocyte recruitment and extravasation during inflammation

Cited by 23 publications

References 39 publications

Fes Tyrosine Kinase Expression in the Tumor Niche Correlates with Enhanced Tumor Growth, Angiogenesis, Circulating Tumor Cells, Metastasis, and Infiltrating Macrophages

Fes Tyrosine Kinase Expression in the Tumor Niche Correlates with Enhanced Tumor Growth, Angiogenesis, Circulating Tumor Cells, Metastasis, and Infiltrating Macrophages

Fer Kinase Limits Neutrophil Chemotaxis toward End Target Chemoattractants

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

Contact Info

Product

Resources

About