Journal
BIOCHEMICAL JOURNAL
Volume 396, Issue -, Pages 89-98Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20051924
Keywords
adhesion; beta 2 integrin; leucocyte recruitment; polymorphonuclear leucocyte; proline-rich tyrosine kinase 2 (Pyk2); Src-family kinase
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Funding
- NHLBI NIH HHS [K08 HL070304, HL070304, R01 HL078663, R01 HL074219, HL074219, HL78663] Funding Source: Medline
- NIDDK NIH HHS [DK064183, R21 DK064183] Funding Source: Medline
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In cell suspensions subjected to high-shear rotatory motion, human PMN (polymorphonuclear cells) adhered to E-selectin-expressing CHO (Chinese-hamster ovary) cells (CHO-E), and formed homotypic aggregates when challenged by E-selectin-IgG fusion protein, by a mechanism that involved beta 2 integrins. Both heterotypic and homotypic PMN adhesion was accompanied by tyrosine phosphorylation of a 110 kDa protein (P110). This event was prevented by blocking anfi-(beta 2 integrin) antibodies and by inhibitors of Src-family kinases, suggesting that it was part of an 'outside-in' signalling that was initiated by integrin engagement. Interestingly, Sre-family kinase inhibitors prevented beta 2-integrin-mediated (i) homotypic PMN adhesion triggered by E-selectin-IgG, (ii) heterotypic CHO-E/PMN adhesion in mixed-cell suspensions, and (iii) firm adhesion of PMN to CHO-E monolayers under physiological flow. Similarly to PMN treated with Sre-family kinase inhibitors, PMN from hck(-/-)fgr(-/-) and hck(-/-)fgr(-/-)lyn(-/-) mice showed significant impairment of beta 2-integrin-mediated adhesion to CHO-E. Moreover, the expression of 2 integrin activation epitopes at the sites of cell-cell contact in CHO-E/ PMN conjugates was abolished by Src-family kinase inhibitors. One component of P110 was identified as the FAK (focal adhesion kinase) Pyk2 (proline-rich tyrosine kinase 2), which was phosphorylated in a 2 integrin- and Src-family-kinase-dependent manner. Thus, Sre-family kinases, and perhaps Pyk2, mediate a signal necessary for beta 2 integrin function in PMN tethered by E-selectin.
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