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Clustering of β2-integrins on human neutrophils activates dual signaling pathways to Ptdlns 3-kinase

Axelsson, Lena LU ; Hellberg, Carina; Melander, Fredrik LU ; Smith, David; Zheng, Limin and Andersson, Tommy LU (2000) In Experimental Cell Research 256(1). p.257-263
Abstract

The β2-integrins on leukocytes can serve as a signaling unit during cell adhesion and locomotion, and to further clarify this important property we investigated the possible mechanisms of β2-integrin-induced activation of PtdIns 3-kinase. It has previously been demonstrated that clustering of β2-integrins activates p21(ras) by a tyrosine kinase-dependent pathway, and here we show that active p21(ras) interacts with its downstream target, PtdIns 3-kinase. Engagement of β2-integrins also activates the tyrosine kinases p58(c-fgr) and p59/61(hck) and causes them to associate with the p85 subunit of PtdIns 3-kinase. These findings suggest a mechanism whereby p58(c- fgr) and p59/61(hck) are directly... (More)

The β2-integrins on leukocytes can serve as a signaling unit during cell adhesion and locomotion, and to further clarify this important property we investigated the possible mechanisms of β2-integrin-induced activation of PtdIns 3-kinase. It has previously been demonstrated that clustering of β2-integrins activates p21(ras) by a tyrosine kinase-dependent pathway, and here we show that active p21(ras) interacts with its downstream target, PtdIns 3-kinase. Engagement of β2-integrins also activates the tyrosine kinases p58(c-fgr) and p59/61(hck) and causes them to associate with the p85 subunit of PtdIns 3-kinase. These findings suggest a mechanism whereby p58(c- fgr) and p59/61(hck) are directly involved in the activation of PtdIns 3- kinase. No coupling between p58(c-fgr) and p59/61(hck) could be detected; hence these kinases probably trigger independent but parallel signals to PtdIns 3-kinase. The effect of β2-integrin clustering on PtdIns 3-kinase activity was monitored as the activation of protein kinase B (PKB). Stimulation of PKB by β2-integrins was abolished by genistein and wortmannin but not by using methyl transferase inhibitors to abrogate the influence of p21(ras)-related proteins. Thus, even if PtdIns 3-kinase is not activated by p21(ras), it can maintain full enzyme activity due to the mentioned interaction with p58(c-fgr) or p59/61(hck). These tyrosine kinases apparently activate similar pathways that operate in parallel and therefore have the potential to substitute for each other in mediating adhesion and regulating cell locomotion. (C) 2000 Academic Press.

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author
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type
Contribution to journal
publication status
published
subject
in
Experimental Cell Research
volume
256
issue
1
pages
7 pages
publisher
Academic Press
external identifiers
  • scopus:0034630470
ISSN
0014-4827
DOI
10.1006/excr.2000.4816
language
English
LU publication?
yes
id
791d845e-4ed8-4c70-978b-416a15b31e2f
date added to LUP
2017-03-10 12:52:43
date last changed
2017-03-10 12:52:43
@article{791d845e-4ed8-4c70-978b-416a15b31e2f,
  abstract     = {<p>The β<sub>2</sub>-integrins on leukocytes can serve as a signaling unit during cell adhesion and locomotion, and to further clarify this important property we investigated the possible mechanisms of β<sub>2</sub>-integrin-induced activation of PtdIns 3-kinase. It has previously been demonstrated that clustering of β<sub>2</sub>-integrins activates p21(ras) by a tyrosine kinase-dependent pathway, and here we show that active p21(ras) interacts with its downstream target, PtdIns 3-kinase. Engagement of β<sub>2</sub>-integrins also activates the tyrosine kinases p58(c-fgr) and p59/61(hck) and causes them to associate with the p85 subunit of PtdIns 3-kinase. These findings suggest a mechanism whereby p58(c- fgr) and p59/61(hck) are directly involved in the activation of PtdIns 3- kinase. No coupling between p58(c-fgr) and p59/61(hck) could be detected; hence these kinases probably trigger independent but parallel signals to PtdIns 3-kinase. The effect of β<sub>2</sub>-integrin clustering on PtdIns 3-kinase activity was monitored as the activation of protein kinase B (PKB). Stimulation of PKB by β<sub>2</sub>-integrins was abolished by genistein and wortmannin but not by using methyl transferase inhibitors to abrogate the influence of p21(ras)-related proteins. Thus, even if PtdIns 3-kinase is not activated by p21(ras), it can maintain full enzyme activity due to the mentioned interaction with p58(c-fgr) or p59/61(hck). These tyrosine kinases apparently activate similar pathways that operate in parallel and therefore have the potential to substitute for each other in mediating adhesion and regulating cell locomotion. (C) 2000 Academic Press.</p>},
  author       = {Axelsson, Lena and Hellberg, Carina and Melander, Fredrik and Smith, David and Zheng, Limin and Andersson, Tommy},
  issn         = {0014-4827},
  language     = {eng},
  number       = {1},
  pages        = {257--263},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Clustering of β2-integrins on human neutrophils activates dual signaling pathways to Ptdlns 3-kinase},
  url          = {http://dx.doi.org/10.1006/excr.2000.4816},
  volume       = {256},
  year         = {2000},
}