Chemokines play a pivotal role in regulating leukocyte migration as well as othef biologic functions. Signaling components following activation of chemokine receptors remain largely undefined. CC chemokine receptor (CCR) 9 is a specific receptor fo|r thymus-expressed CC chemokine, TECK (e.g., Youn et al Blood 94:2533, 1999). We no\Lshow that engagement of CCR9 with TECK leads to activation of Akt (protein kinase E|, PKB), mitogen-activated protein kinases (MAPK), glycogen synthase kinase-3bet (GSK-3beta), and a forkhead transcription factor, FKHR in a human T cell line, MOLT.4. When CCR9 is expressed by itself or along with Akt in Cos7 cells, stimulation with TECIp activates Akt. Using chemical inhibitors, it is shown that PI3 kinase, but not MAPK, ils required for CCR9-mediated cell migration. Akt, GSK-3beta, FKHR and MAPK hav been previously implicated in cell survival signals in response to an array of death stimul. When MOLT4 cells, which naturally express CCR9 as well as Fas, were stimulated win the agonistic Fas antibody, CH-11, these cells underwent apoptosis. However, stimulation of MOLT4 cells with TECK significantly blocked Fas-mediated cell death. Pretreatment of the MOLT4 cells with wortmannin, but not with PD98059, restored the ability of Fas to induce apoptosis, suggesting that PI3 kinases, but not MAPK, accounts for CCR9mediated cell survival against Fas-induced apoptosis. This, we believe, is the firslt demonstration that activation of a chemokine receptor leads to phosphorylation o|f GSK-3beta and FKHR, and demonstrates a mechanistic example of how chemokines cak take part in a biologic function other than chemotaxis.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology