A PKCβ-LYN-PYK2 Signaling Axis Is Critical for MCP-1-Dependent Migration and Adhesion of Monocytes

MCP-1-induced monocyte chemotaxis is a crucial event in inflammation and atherogenesis. Identifying the important signal transduction pathways that control monocyte chemotaxis can unravel potential targets for preventive therapies in inflammatory disease conditions. Previous studies have shown that...

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Published in:	The Journal of immunology (1950) Vol. 206; no. 1; pp. 181 - 192
Main Authors:	Das, Pradip, Pal, Srabani, Oldfield, Claudine M, Thillai, Kowsalya, Bala, Sinjini, Carnevale, Kevin A, Cathcart, Martha K, Bhattacharjee, Ashish
Format:	Journal Article
Language:	English
Published:	United States 01-01-2021
Subjects:	Cell Adhesion Cells, Cultured Chemokine CCL2 - genetics Chemokine CCL2 - metabolism Chemotaxis Focal Adhesion Kinase 2 - metabolism Humans Monocytes - physiology Multiprotein Complexes - metabolism Phosphorylation Primary Cell Culture Protein Kinase C beta - metabolism Proto-Oncogene Proteins pp60(c-src) - metabolism Signal Transduction src-Family Kinases - metabolism
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Summary:	MCP-1-induced monocyte chemotaxis is a crucial event in inflammation and atherogenesis. Identifying the important signal transduction pathways that control monocyte chemotaxis can unravel potential targets for preventive therapies in inflammatory disease conditions. Previous studies have shown that the focal adhesion kinase Pyk2 plays a critical role in monocyte motility. In this study, we investigated the MCP-1-mediated activation of Pyk2 (particularly by the phosphorylation of Tyr ) in primary human peripheral blood monocytes. We showed that MCP-1 induces Src phosphorylation in a similar time frame and that the MCP-1-induced Pyk2 tyrosine phosphorylation is controlled by the Src family kinase. We also report, in this study, that PKCβ, an isoform of PKC, is required for both Src and Pyk2 activation/phosphorylation in response to MCP-1 stimulation. We identified Lyn as the specific Src kinase isoform that is activated by MCP-1 and acts upstream of Pyk2 in primary monocytes. Furthermore, Lyn is found to be indispensable for monocyte migration in response to MCP-1 stimulation. Moreover, our coimmunoprecipitation studies in monocytes revealed that PKCβ, Pyk2, and Lyn exist constitutively in a molecular complex. To our knowledge, our study has uncovered a novel PKCβ-Lyn-Pyk2 signaling cascade in primary monocytes that regulates MCP-1-induced monocyte adhesion and migration.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1900706