J Immunol 2003,
PMID: 12794117
Rose, David M; Liu, Shouchun; Woodside, Darren G; Han, Jaewon; Schlaepfer, David D; Ginsberg, Mark H
Engagement of very late Ag-4 (integrin alpha(4)beta(1)) by ligands such as VCAM-1 markedly stimulates leukocyte migration mediated by LFA-1 (integrin alpha(L)beta(2)). This form of integrin trans-regulation in T cells requires the binding of paxillin to the alpha(4) integrin cytoplasmic domain. This conclusion is based on the abolition of trans-regulation in Jurkat T cells by an alpha(4) mutation (alpha(4)(Y991A)) that disrupts paxillin binding. Furthermore, cellular expression of an alpha(4)-binding fragment of paxillin that blocks the alpha(4)-paxillin interaction, selectively blocked VCAM-1 stimulation of alpha(L)beta(2)-dependent cell migration. The alpha(4)-paxillin association mediates trans-regulation by enhancing the activation of tyrosine kinases, focal adhesion kinase (FAK) and/or proline-rich tyrosine kinase-2 (Pyk2), based on two lines of evidence. First, disruption of the paxillin-binding site in the alpha(4) tail resulted in much less alpha(4)beta(1)-mediated phosphorylation of Pyk2 and FAK. Second, transfection with cDNAs encoding C-terminal fragments of Pyk2 and FAK, which block the function of the intact kinases, blocked alpha(4)beta(1) stimulation of alpha(L)beta(2)-dependent migration. These results define a proximal protein-protein interaction of an integrin cytoplasmic domain required for trans-regulation between integrins, and establish that augmented activation of Pyk2 and/or FAK is an immediate signaling event required for the trans-regulation of integrin alpha(L)beta(2) by alpha(4)beta(1).
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
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NCI Pathway Database Alpha4 beta1 integrin signaling events:
alpha4/beta1 Integrin/VCAM1/Paxillin complex (VCAM1-PXN-ITGA4-ITGB1)
→
FAK (PTK2)
(modification, activates)
Evidence: mutant phenotype
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NCI Pathway Database Alpha4 beta1 integrin signaling events:
alpha4/beta1 Integrin/VCAM1/Paxillin complex (VCAM1-PXN-ITGA4-ITGB1)
→
PYK2 (PTK2B)
(modification, activates)
Evidence: mutant phenotype
In total, 14 gene pairs are associated to this article in curated databases