Abstract
BackgroundAmyloid precursor protein (APP) is a ubiquitously expressed cell surface protein reported to be involved in mediating cell-cell or cell-matrix interactions. Prior work has demonstrated that APP co-localizes with β1 integrin in different cell types.MethodsIn an effort to determine the function of APP on monocytic lineage cells, in particular, the human monocyte cell line, THP-1, was used to assess the role of APP during adhesion to the extracelluar matrix component type I collagen.ResultsPull-down assays demonstrated that THP-1 adhesion to collagen stimulated a tyrosine kinase-associated signaling response which included subsequent phosphorylation of p38 MAP kinase and increased association of APP with α2β1 integrin, specifically. In addition, cell adhesion was dependent upon APP expression since APP siRNA knockdown attenuated THP-1 adhesion to collagen compared to mock transfected controls. One consequence of the tyrosine kinase-dependent signaling response was increased secretion of interleukin-1β (IL-1β) and Aβ1-40 but not the Aβ1-42 fragment of APP. Increased secretion of IL-1β was dependent upon p38 MAP kinase activity while Aβ1-40 secretion required Src family kinase activity since the specific p38 inhibitor, SB202190, and the Src family kinase inhibitor, PP2, attenuated IL-1β and Aβ1-40 secretion, respectively.ConclusionsThese data demonstrate that APP is involved in classic integrin-dependent tyrosine kinase-associated adhesion and activation of peripheral monocytic cells. Moreover, divergent APP-dependent signaling is required for increased secretion of both IL-1β and Aβ1-40 as a component of the adhesion-dependent change in phenotype. This suggests that APP may have a broad role in not only mediating cell-matrix adhesion but also in the function of peripheral immune cells.
Highlights
Amyloid precursor protein (APP) is a ubiquitously expressed cell surface protein reported to be involved in mediating cell-cell or cell-matrix interactions
Since tyrosine kinase activation is necessary for downstream activation of the p38 mitogen-activated protein kinase (MAPK) pathway as well as subsequent increases in proinflammatory protein levels [7], it was determined whether the adhesion-dependent changes in APP processing were dependent on this signaling
We previously demonstrated that b1 integrin ligation on monocytes stimulates increased tyrosine kinase activity, recruitment of tyrosine kinases Lyn and Syk to APP, and a reactive phenotype [7]. b1 integrins form heterodimeric receptors with different a subunits and the specific combination of ab subunits dictates both binding specificity and overall function of the receptor [38]
Summary
Amyloid precursor protein (APP) is a ubiquitously expressed cell surface protein reported to be involved in mediating cell-cell or cell-matrix interactions. Prior work has demonstrated that APP co-localizes with b1 integrin in different cell types. The progressive accumulation of extracellular beta amyloid-containing plaques is a cardinal feature of Alzheimer’s disease (AD) pathology. Several data support a role for APP in adhesion including evidence that APP co-localizes with b1 integrins in both neurons and monocytes as well as evidence that APP binds directly to type I collagen and other extracellular matrix (ECM) molecules [5,6,7,8]. Monocytes closely interact with extracellular matrix components, in part through integrin receptor interaction, which can further activate these cells towards macrophage differentiation [15,16,17]. In vitro exposure of endothelial cells to Ab1-40 up-regulates endothelial adhesion molecule expression and monocytic adhesion to these cells, facilitating the transmigration process [22]
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