Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation

Ahr, Barbara; Denizot, Mélanie; Robert-Hebmann, Véronique; Brelot, Anne; Biard-Piechaczyk, Martine

doi:10.1074/jbc.m408481200

Cited by 65 publications

(73 citation statements)

References 83 publications

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“…The chemokine receptor CXCR4 was described to activate the JAK2/STAT3 pathway in different cell lines (Vila-Coro et al, 1999;Soriano et al, 2003;Opdam et al, 2004;Moriguchi et al, 2005) and the intracellular domains responsible for JAK2 binding have been discovered by mutational analysis (Ahr et al, 2005). Until now, there has been no report on the activation of the JAK/STAT pathway in SCLC.…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation with CXCL12 leads to activation of various pathways in SCLC cells, and CXCR4 has also been reported to activate the JAK/STAT3 pathway (Vila-Coro et al, 1999;Ahr et al, 2005). Signal transducers and activators of transcription (STAT) proteins are latent transcription factors that become activated by phosphorylation on a specific tyrosine residue by JAK-family kinases (Darnell, 1997).…”

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confidence: 99%

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Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

et al. 2009

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Small cell lung cancer (SCLC) is an aggressive, rapidly metastasising tumour. Previously, we demonstrated the influence of CXCL12 -CXCR4 interaction on processes involved in metastasis and chemoresistance in SCLC. We show here that STAT3 is expressed in both primary SCLC tumour tissues and SCLC cell lines. We investigated the function of STAT3 upon CXCL12 stimulation in SCLC cell lines. Small cell lung cancer cell lines present constitutive phosphorylation of STAT3, and in the reference cell lines NCI-H69 and NCI-H82 constitutive phosphorylation was further increased by CXCL12 stimulation. Further investigating this signalling cascade, we showed that it involves interactions between CXCR4 and JAK2 in both cell lines. However CXCL12-induced adhesion to VCAM-1 could be completely inhibited by the JAK2 inhibitor AG490 only in NCI-H82. Furthermore, CXCR4 antagonist but not AG490 inhibited cell adhesion whereas both antagonisms were shown to inhibit growth of the cells in soft agar, indicating the central involvement of this signalling in anchorage-independent growth of SCLC cells. Most interestingly, while using primary tumour material, we observed that in contrast to non-small-cell lung cancer samples from primary tumour tissues, all analysed samples from SCLC were strongly positive for tyrosine-phosphorylated STAT3. Taken together, these data indicate that STAT3 is constitutively phosphorylated in SCLC and is important in SCLC growth and spreading thus presenting an interesting target for therapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

et al. 2009

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“…Anti-SDF-1 neutralizing antibody inhibits growth of CXCR4 positive xenografts in the presence of CAFs. 32 SDF-1 binding to CXCR4 can activate Akt, 34 transactivate epidermal growth factor receptor, 35 activate JAK2/STAT3 leading to enhanced survival and inhibition of apoptosis 36 and alter ras signaling. 37 SDF-1 signaling also induces production of the matrix metalloproteinases MMP-2, MMP-9 38 and MMP-13 39 that are important for breaking down basement membrane.…”

Section: Discussionmentioning

confidence: 99%

Dynamic stromal‐epithelial interactions during progression of MCF10DCIS.com xenografts

Tait

Pauley

Santner

et al. 2007

Intl Journal of Cancer

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cells form comedo type ductal carcinoma in situ in immune-deficient mice before forming invasive ductal carcinoma. As the lesions mature, both stromal and epithelial cells undergo phenotypic changes detected by immunohistochemistry. Myofibroblasts are present before the formation of carcinoma in situ and after development of invasive carcinoma. MCF10DCIS. com lesions develop a myoepithelial layer prior to exhibiting a basement membrane surrounding the ductal mass. TGFb1 is initially expressed by the epithelial cells but is expressed by stroma in invasive carcinoma. Stromal derived factor-1 is detected in epithelial cells in early carcinoma in situ but is produced in stromal cells in invasive carcinoma. The receptor CXCR4 is expressed by epithelial cells in the xenografts at all times, as is the hepatocyte growth factor receptor c-met. MCF10DCIS.com xenografts illustrate the dynamic interplay of epithelium and stroma in the development of carcinoma in situ and subsequent invasive carcinoma. Although the phenotype of the epithelial cells may be dependent upon the stroma, the malignant epithelium induces the development of the stroma necessary for progression to the invasive stage. ' 2007 Wiley-Liss, Inc.Key words: breast cancer; carcinoma in situ; MCF10DCIS.com; progression; stroma; xenograft The natural history of cancer is thought to involve multiple sequential genetic changes including mutations, loss of heterozygosity and amplification of gene copy number as well as epigenetic changes such as hypermethylation of promoter regions. In many epithelial cancers a series of abnormal histologic changes can be identified and associated with increased risk of progressing to malignant disease. It has been assumed that each stage accumulates additional genetic anomalies. The first recognized lesion with increased risk for breast cancer is hyperplasia ( a 4-fold increased risk for atypical ductal hyperplasia) but genetic anomalies are rare. ErbB2 is rarely detected in benign lesions. 1-3 However, overexpression of erbB2 is frequent in DCIS and IDC. Studies of mixed lesions, containing both in situ and invasive components, invariably report that the 2 components express erbB2 coordinately. 4-6 A similar pattern occurs for cyclin D1 expression; rare in benign hyperplastic lesions but frequent in both DCIS and IDC and expressed coordinately in both in situ and invasive components of mixed lesions. 7,8 Recent studies suggest that nearly all genetic alterations have occurred by the time of DCIS formation. Comparative genomic hybridization analysis of breast DCIS and IDC found no significant difference in the number of chromosomal abnormalities, although the frequency of a few specific changes varied in high grade versus low grade DCIS and between DCIS and concurrent IDC. 9 A more recent study confirmed that DCIS is genetically advanced. Allelic imbalance of 52 microsatellite markers of chromosomal regions commonly lost in breast cancer increased significantly between atypical ductal hyperplasia and DCIS but not between DCIS an...

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“…Immune-deficient mice injected with LCLs survive longer with neutralizing CXCL12 antibody or with inhibition of CXCR4 signaling. Ex vivo lymphoma cell treatment with CXCL12 neutralizing antibody or CXCR4 antagonists decreases cell proliferation and increases apoptosis (50), whereas CXCL12 induced CXCR4-mediated JAK2 activation and STAT3 phosphorylation (62). Phosphorylated STAT3 binding to DNA activates genes important for proliferation, survival, and angiogenesis and suppresses tumor immune responses (63).…”

Section: Ebna3c-regulated Genes Overlap With Ebna2-and Ebna3a-regulatedmentioning

confidence: 99%

Epstein–Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines

Mar¹,

Maruo

Lee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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EBV nuclear antigen 3C (EBNA3C) is an essential transcription factor for EBV transformed lymphoblast cell line (LCL) growth. To identify EBNA3C-regulated genes in LCLs, microarrays were used to measure RNA abundances in each of three different LCLs that conditionally express EBNA3C fused to a 4-OH-Tamoxifen-dependent estrogen receptor hormone binding domain (EBNA3CHT). At least three RNAs were assayed for each EBNA3CHT LCL under nonpermissive conditions, permissive conditions, and nonpermissive conditions with wild-type EBNA3C transcomplementation. Using a two-way ANOVA model of EBNA3C levels, we identified 550 regulated genes that were at least 1.5-fold up-or down-regulated with false discovery rates < 0.01. EBNA3C-regulated genes overlapped significantly with genes regulated by EBNA2 and EBNA3A consistent with coordinated effects on cell gene transcription. Of the 550 EBNA3C-regulated genes, 106 could be placed in protein networks. A seeded Bayesian network analysis of the 80 most significant EBNA3C-regulated genes suggests that RAC1, LYN, and TNF are upstream of other EBNA3C-regulated genes. Gene set enrichment analysis found enrichment for MAP kinase signaling, cytokine-cytokine receptor interactions, JAK-STAT signaling, and cell adhesion molecules, implicating these pathways in EBNA3C effects on LCL growth or survival. EBNA3C significantly up-regulated the CXCL12 ligand and its CXCR4 receptor and increased LCL migration. CXCL12 up-regulation depended on EBNA3C's interaction with the cell transcription factor, RBPJ, which is essential for LCL growth. EBNA3C also up-regulated MYC 1.3-fold and down-regulated CDKN2A exons 2 and 3, shared by p16 and p14, 1.4-fold, with false discovery rates < 5 × 10 −4 . lymphoma | Notch

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Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation

Cited by 65 publications

References 83 publications

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

Dynamic stromal‐epithelial interactions during progression of MCF10DCIS.com xenografts

Epstein–Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines

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