1: J Biol Chem. 2005 Feb 25;280(8):6692-700. Epub 2004 Dec 22. 

Identification of the cytoplasmic domains of CXCR4 involved in Jak2 and STAT3
phosphorylation.

Ahr B, Denizot M, Robert-Hebmann V, Brelot A, Biard-Piechaczyk M.

Laboratoire Infections Retrovirales et Signalisation Cellulaire, CNRS UMR 5121,
Institut de Biologie, 4, Bd Henri IV, CS 89508, 34960 Montpellier Cedex 2,
France.

The chemokine SDF-1alpha transduces G(i)-dependent and -independent signals
through CXCR4. Activation of Jak2/STAT3, a G(i)-independent signaling pathway,
which plays a major role in survival signals, is known to be activated after
SDF-1alpha binding to CXCR4 but the domains of CXCR4 involved in this signaling
remain unexplored. Using human embryonic kidney HEK-293 cells stably expressing
wild-type or mutated forms of CXCR4, we demonstrated that STAT3 phosphorylation
requires the N-terminal part of the third intracellular loop (ICL3) and the
tyrosine 157 present at the end of the second intracellular loop (ICL2) of
CXCR4. In contrast, neither the conserved Tyr(135) in the DRY motif at the N
terminus of ICL2 nor the Tyr(65) and Tyr(76) in the first intracellular loop
(ICL1) are involved in this activation. ICL3, which does not contain any
tyrosine residues, is needed to activate Jak2. These results demonstrate that
two separate domains of CXCR4 are involved in Jak2/STAT3 signaling. The
N-terminal part of ICL3 is needed to activate Jak2 after SDF-1alpha binding to
CXCR4, leading to phosphorylation of only one cytoplasmic Tyr, present at the C
terminus of ICL2, which triggers STAT3 activation. This work has profound
implications for the understanding of CXCR4-transduced signaling.

PMID: 15615703 [PubMed - indexed for MEDLINE]


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2: J Neurochem. 2004 Aug;90(3):750-7. 

Beta-naphthoflavone disturbs astrocytic differentiation of C6 glioma cells by
inhibiting autocrine interleukin-6.

Takanaga H, Yoshitake T, Yatabe E, Hara S, Kunimoto M.

Department of Public Health, School of Pharmaceutical Sciences, Kitasato
University, Tokyo, Japan. mt375@cam.ac.uk

Regulation of astrocyte differentiation is a key process in the development of
the central nervous system (CNS), and disturbance of the differentiation can
lead to brain system dysfunction. Here we show that beta-naphthoflavone
(betaNF), an agonist of the aryl hydrocarbon receptor (AhR), disturbed the
cAMP-induced astrocytic differentiation of C6 glioma by inhibiting autocrine
interleukin-6 (IL-6). Treatment of cells with betaNF reduced the induction of an
astrocyte marker glial fibrillary acidic protein (GFAP). This was caused by the
inactivation of its upstream transcription factor signal transducer and
activator of transcription 3 (STAT3) by betaNF. In addition, betaNF attenuated
the induction of the IL-6 gene, which leads to the activation of STAT3. Most
importantly, the inhibitory effect of betaNF on GFAP promoter activity was
recovered by the addition of recombinant IL-6. Taken together, these results
indicate that the inhibitory effect of betaNF on IL-6 induction suppresses STAT3
activation. These processes subsequently lead to the attenuation of GFAP
induction.

PMID: 15255954 [PubMed - indexed for MEDLINE]


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