
<ArticleTitle>Blocking of c-FLIP(L)--independent cycloheximide-induced apoptosis or <prot>Fas</prot>-mediated apoptosis by the <prot>CC chemokine receptor 9</prot>/<prot>TECK</prot> interaction.</ArticleTitle>
<AbstractText>Chemokines play a pivotal role in regulating leukocyte migration as well as other biological functions. <prot>CC chemokine receptor 9</prot> (<prot>CCR9</prot>) is a specific receptor for <prot>thymus-expressed CC chemokine</prot> (<prot>TECK</prot>). It is shown here that engagement of <prot>CCR9</prot> with <prot>TECK</prot> leads to phosphorylation of <prot>Akt</prot> (<prot>protein kinase B</prot>), <prot>mitogen-activated protein kinase</prot>s (<prot>MAPK</prot>s), <prot>glycogen synthase kinase--3 beta</prot> (<prot>GSK-3 beta</prot>), and a <prot>forkhead transcription factor</prot>, <prot>FKHR</prot>, in a human T-cell line, MOLT4, that naturally expresses <prot>CCR9</prot>. By means of chemical inhibitors, it is shown that <prot>phosphoinositide-3 kinase</prot> (<prot>PI-3 kinase</prot>), but not <prot>MAPK</prot>, is required for <prot>CCR9</prot>-mediated chemotaxis. <prot>Akt</prot>, <prot>GSK-3 beta</prot>, <prot>FKHR</prot>, and <prot>MAPK</prot> have been previously implicated in cell survival signals in response to an array of death stimuli. When MOLT4 cells, which expressed <prot>Fas</prot> as well as <prot>CXCR4</prot>, were stimulated with cycloheximide (CHX), an agonistic anti-Fas antibody, or a combination of these, the cells rapidly underwent apoptosis. However, costimulation of MOLT4 cells with <prot>TECK</prot> or <prot>stromal derived factor--1</prot> significantly blocked CHX-mediated apoptosis, whereas stimulation only with <prot>TECK</prot> partially blocked Fas-mediated apoptosis. Concomitant with this blocking, cleavage of <prot>poly (adenosine 5'-diphosphate--ribose) polymerase</prot> and activation of <prot>caspase 3</prot> were significantly attenuated, but the expression level of <prot>FLICE inhibitory protein</prot> <prot>c-FLIP(L)</prot>, which had been shown to be regulated by CHX, was unchanged. This demonstrates that activation of <prot>CCR9</prot> leads to phosphorylation of <prot>GSK-3</prot> beta and <prot>FKHR</prot> and provides a cell survival signal to the receptor expressing cells against CHX. It also suggests the existence of a novel pathway leading to CHX-induced apoptosis independently of <prot>c-FLIP(L)</prot>. (Blood. 2001;98:925-933)</AbstractText>
