Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity.

Abstract

Podosomes are protrusive structures implicated in macrophage extracellular matrix degradation and three-dimensional migration through cell barriers and the interstitium. Podosome formation and assembly are regulated by cytoskeleton remodeling requiring cytoplasmic tyrosine kinases of the Src and the Abl families. Considering that Abl has been reported to phosphorylate the guanine nucleotide exchange factor Sos1, eliciting its Rac-guanine nucleotide exchange factor activity, and Rac regulates podosome formation in myeloid cells and invadopodia formation in cancer cells, we addressed whether Sos1 is implicated in podosome formation and function in macrophages. We found that ectopically expressed Abl or the Src kinase Fgr phosphorylate Sos1, and the Src kinases Hck and Fgr are required for Abl and Sos1 phosphorylation and Abl/Sos1 interaction in macrophages. Sos1 localizes to podosomes in both murine and human macrophages, and its silencing by small interfering RNA results in disassembly of murine macrophage podosomes and a marked reduction of GTP loading on Rac. Matrix degradative capacity, three-dimensional migration through Matrigel, and transmigration through an endothelial cell monolayer of Sos1-silenced macrophages were inhibited. In addition, Sos1- or Abl-silenced macrophages, or macrophages treated with the selective Abl inhibitor imatinib mesylate had a reduced capability to migrate into breast tumor spheroids, the majority of cells remaining at the margin and the outer layers of the spheroid itself. Because of the established role of Src and Abl kinases to regulate also invadopodia formation in cancer cells, our findings suggest that targeting the Src/Abl/Sos1/Rac pathway may represent a double-edged sword to control both cancer-invasive capacities and cancer-related inflammation.

• Authors: Anna Baruzzi, Sabrina Remelli, Erika Lorenzetto, Michela Sega, Roberto Chignola, Giorgio Berton
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 10 Pg. 4900-12 (Nov 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26447228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Proto-Oncogene Proteins
• SOS1 Protein
• Imatinib Mesylate
• Proto-Oncogene Proteins c-abl
• proto-oncogene proteins c-fgr
• src-Family Kinases
• rac GTP-Binding Proteins

Topics

• Animals
• COS Cells
• Cell Movement (drug effects, genetics, immunology)
• Chlorocebus aethiops
• Humans
• Imatinib Mesylate (pharmacology)
• Macrophages (immunology, pathology)
• Mice
• Neoplasm Invasiveness (genetics, immunology)
• Neoplasms (genetics, immunology, pathology)
• Phosphorylation (drug effects, genetics, immunology)
• Podosomes
• Proto-Oncogene Proteins (genetics, immunology)
• Proto-Oncogene Proteins c-abl (antagonists & inhibitors, genetics, immunology)
• SOS1 Protein (genetics, immunology)
• rac GTP-Binding Proteins (genetics, immunology)
• src-Family Kinases (genetics, immunology)