Paracrine Signaling through the JAK/STAT Pathway Activates Invasive Behavior of Ovarian Epithelial Cells in Drosophila

Silver, Debra L.; Montell, Denise J.

doi:10.1016/s0092-8674(01)00607-9

Cited by 285 publications

(385 citation statements)

References 49 publications

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“…Whereas this transition phase is an essential first step for cell migration, it is poorly understood at the molecular level. Specification of the migratory cell fate in the case of border cells depends on the function of the JAK-STAT pathway (Beccari et al, 2002;Silver and Montell, 2001), while neural crest cell migration depends on proteins of the Snail family (Nieto, 2001). Nevertheless, the molecules that are directly involved in the transition are unknown.…”

Section: Discussionmentioning

confidence: 99%

Transition from non-motile behaviour to directed migration during early PGC development in zebrafish

Blaser

Eisenbeiß

Neumann

et al. 2005

Journal of Cell Science

167

189

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The migration of zebrafish primordial germ cells (PGCs) is directed by SDF-1a and serves as a model for long-range chemokine-guided cell migration. Whereas the development and migration of zebrafish PGCs have been studied in great detail starting at mid-gastrulation stages when the cells exhibit guided active migration [7-8 hours post fertilization (hpf)], earlier stages have not yet been examined. Here we show that the PGCs acquire competence to respond to the chemokine following discrete maturation steps. Using the promoter of the novel gene askopos and RNA elements of nanos1 to drive GFP expression in PGCs, we found that immediately after their specification (about 3 hpf) PGCs exhibit simple cell shape. This stage is followed by a phase at which the cells assume complex morphology yet they neither change their position nor do they respond to SDF-1a. During the third phase, a transition into a `migratory stage' occurs as PGCs become responsive to directional cues provided by somatic cells secreting the chemokine SDF-1a. This transition depends on zygotic transcription and on the function of the RNA-binding protein Dead end and is correlated with down regulation of the cell adhesion molecule E-cadherin. These distinctive morphological and molecular alterations could represent a general occurrence in similar processes critical for development and disease.

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Section: Discussionmentioning

confidence: 99%

Transition from non-motile behaviour to directed migration during early PGC development in zebrafish

Blaser

Eisenbeiß

Neumann

et al. 2005

Journal of Cell Science

167

189

View full text Add to dashboard Cite

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“…Loss-offunction clones were induced in: y,w,p{ry þ ,hs-FLP}1/y,w;p {neo r , FRT}82B,p{Ubq-GFP}83/p{neo r ,FRT}82B, STAT92E 06346 , ry 506 (Hou et al, 1996), y,w,p{ry þ ,hs-FLP}1/y,w;p{neo r , FRT} 82B,p{Ubq-GFP}83/p{neo r ,FRT}82B, STAT92E 397 , e (Silver and Montell, 2001), y,w,p{ry þ ,hs-FLP}1/y,w;p{neo r , FRT}82B,p {Ubq-GFP}83/p{neo r ,FRT}82B, p{w þ ,arm-lacZ}, y, w, f 36a ; p{ry þ ,hs-FLP38}/ þ ;p{neo r ,FRT}82B, p{f þ }87F, STAT92E 06346 / p{neo r ,FRT}82B, p{y þ ,Car20y}96E or y,w,hop C111 ,p{neor, FRT}18A/w, p[w þ ,Ubq-GFP], ,p{neo r ,FRT}18A; p[ry þ , hs-FLP}38/ þ . Gain-of-function clones were induced in larvae resulting from the cross between y,w; p{w þ ,Act>y þ >Gal4}, p{w þ ,UAS-nGFP}/SM5a-TM6b (Ito et al, 1997) and either y,w,p{ry þ ,hs-FLP}1;p{w þ ,UAS-upd} (Zeidler et al, 1999), y,w,p{ry þ ,hs-FLP}1;p{w þ ,UAS-hop} (Binari and Perrimon, 1994), y,w,p{ry þ ,hs-FLP}1;p{w þ ,UAS-DomeDCyt} (Brown et al, 2001), y,w,p{ry þ ,hs-FLP}1;p{w þ ,UAS-DNSTAT92E} (Henriksen et al, 2002) or y,w,p{ry þ ,hs-FLP}1 (Golic, 1991).…”

Section: Methodsmentioning

confidence: 99%

“…Strikingly, 5471 h AEL clones are only slightly smaller than their twin clones (Table 1), while 7271 h AEL clones, which have grown throughout third instar development (and are subsequently termed 'late clones'), appear to have overproliferated and are on average 161785% the size of their wild-type twin clone controls ( Figure 2d; Table 1). In order to exclude potential genetic background effects as a cause for this change, the independent amorphic allele, STAT92E 397 (Silver and Montell, 2001) was also tested and found to produce a similar overgrowth effect while control experiments using a wild-type chromosome showed no differences in clone size (Table 1). Statistically, the areas of STAT92E mutant clones of both alleles are significantly larger than wild-type controls (Table 1) (Po0.01).…”

Section: Cellular Proliferation In Stat92e Mutant Clonesmentioning

confidence: 99%

Opposing roles for Drosophila JAK/STAT signalling during cellular proliferation

2005

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The JAK/STAT signalling pathway mediates both antiproliferative responses following interferon stimulation and cellular proliferation in response to cytokines such as interleukins and growth factors. Central to these responses are the seven vertebrate STAT molecules, misregulation of which is implicated in a variety of malignancies. We have investigated the proliferative role of the single Drosophila STAT92E, part of the evolutionarily conserved JAK/STAT cascade. During second instar larval wing disc development pathway activity is both necessary and sufficient to promote proliferation of this epithelial cell type. However by later stages, endogenous STAT92E is stimulated by a noncannonical mechanism to exert pronounced antiproliferative effects. Ectopic canonical activation is sufficient to further decrease proliferation and leads to the premature arrest of cells in the G2 phase of the cell cycle. The single STAT92E present in Drosophila therefore mediates both proproliferative functions analogous to vertebrate interleukin-stimulated STAT3 and antiproliferative functions analogous to interferon-stimulated STAT1. Pro-and antiproliferative roles therefore represent ancestral activities conserved through evolution and subsequently assigned to distinct molecules.

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“…Mouse keratinocytes conditionally depleted of STAT3 show defects in wound healing (Sano et al, 1999). Activation of JAK/STAT pathway in the Drosophila ovary causes the 'extra cells' to become invasive, while the migration of a subset of epithelial follicular cells called the 'border cells' is dependent on STAT expression (Silver and Montell, 2001). As initiation of the human ovarian cancer postulated to originate from the ovarian surface epithelium with subsequent exfoliation of tumour cells in the peritoneum somewhat resembles the situation in the Drosophila ovary, it is not surprising that several of the genes that control Drosophila epithelial follicle cell migration are homologous to genes implicated in the progression of ovarian cancer (Montell, 2003).…”

mentioning

confidence: 99%

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

et al. 2008

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Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelialmesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of b-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF-and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer.

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Paracrine Signaling through the JAK/STAT Pathway Activates Invasive Behavior of Ovarian Epithelial Cells in Drosophila

Cited by 285 publications

References 49 publications

Transition from non-motile behaviour to directed migration during early PGC development in zebrafish

Transition from non-motile behaviour to directed migration during early PGC development in zebrafish

Opposing roles for Drosophila JAK/STAT signalling during cellular proliferation

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

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