Constitutive Activation of JAK1 in Src-transformed Cells

Campbell, George S.; Yu, Chao‐Lan; Jove, Richard; Carter‐Su, Christin

doi:10.1074/jbc.272.5.2591

Cited by 98 publications

(93 citation statements)

References 31 publications

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“…Several groups have reported that v-src and Src-kinase can activate STAT3 (Cao et al, 1996;Campbell et al, 1997;Chaturvedi et al, 1998). In addition, Marrero et al (1995) reported that activation of STAT3 can be induced or enhanced by GCRs, in particular by angiotensin II AT 1 receptor.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, we found that v-fms induces constitutive tyrosine phosphorylation of STAT3 in cells with active G i2 and Src proteins, but not in cells with de®cient G i2 and/or Src proteins, indicating that v-fms requires Src to activate STAT3 and that Src-mediated activation of STAT3 may be the decisive event regulated by G i2 proteins in the transduction of CSF-1R signalling. However, although Src was reported to interact directly with STAT3 in several cell types (Cao et al, 1996;Campbell et al, 1997;Chaturvedi et al, 1998), in NIH3T3 cells Src and STAT3 could not be co-precipitated with anti-Src or anti-STAT3 antibodies (not shown). In our model, inactivation of G i2 proteins and/or Src-kinase was accompanied by increased expression of truncated forms of STAT3: 85 kDa STAT3D was constitutively expressed, whereas 70 kDa STAT3D, a cytosolic, C-and N-terminal truncated, unconstantly expressed form, appears to be the result of proteolysis.…”

Section: Discussionmentioning

confidence: 96%

“…The regulation of Src-kinase activity by G i2 proteins is speci®c: Fyn expression and activity were not altered in cells expressing a i2 -G204A, indicating that Fyn did not compensate for Src in signalling leading to cell proliferation. Indeed, the role played by Src in the regulation of cell proliferation is thought to be essential: it was reported that Src stimulates JAK1 and STAT3 (Cao et al, 1996 ;Campbell et al, 1997;Chaturvedi et al, 1998) and also that impaired ®broblast proliferation related to de®cient Src-kinase activity could be rescued by c-myc (Roche et al, 1995b). In our model, we found no evidence linking Src activity and c-myc expression; v-fms expression increased c-myc levels to similar levels in cells with active or inactive G i2 proteins (i.e., intact or de®cient Src-kinase activity).…”

Section: Discussionmentioning

confidence: 99%

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Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

1999

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We previously showed that G i2 proteins interfere with the transduction of CSF-1 receptor (CSF-1R) proliferation signals (Corre and Hermouet, 1995). To identify CSF-1R pathways controlled by G i2 , we transfected v-fms, the oncogenic equivalent of CSF-1R, in NIH3T3 cells in which G i2 proteins were inactivated by stably expressing a dominant negative mutant form of the a subunit of G i2 (a i2 -G204A). Expression of a i2 -G204A resulted in decreased Src-kinase activity, delayed activation of p42 ERK-MAPK, decreased cyclin D1 expression and reduced proliferation in response to serum. In a i2 -G204A cells transfected with v-fms, Src-kinase activity remained de®cient but p42 MAPK activity and cyclin D1 expression were similar to those of vector/v-fms cells, suggesting that v-fms bypasses Src to activate the ERK-MAPK cascade. However, DNA synthesis and focus formation were inhibited by up to 80% in a i2 -G204A/vfms cells compared to vector/v-fms cells. We found that tyrosine phosphorylation of STAT3, also activated by CSF-1R/v-fms, was inhibited in a i2 -G204A/v-fms cells; in addition, expression of an 85 kDa, C-terminal truncated form of STAT3 (STAT3D) was constitutively increased. Both the inhibition of v-fms-induced STAT3 tyrosine phosphorylation and the increased expression of STAT3D were reproduced by transfecting a dominant negative mutant of Src. Last, we show that expression of STAT3D55C, a mutant form of STAT3 lacking the last 55 C-terminal amino acids, is su cient to inhibit DNA synthesis and v-fms-induced transformation in NIH3T3 cells. In summary, adequate regulation by G i2 proteins of the activity of both Src-kinase and STAT3 is required for optimal cell proliferation in response to CSF-1R/vfms.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

1999

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“…Though the upstream e ectors of Stat3 are not completely understood, JAKs are believed to be responsible for the tyrosine phosphorylation of Stat3 in response to growth factors and cytokines, as well as in Src-transformed cells (Briscoe et al, 1996;Campbell et al, 1997;Zhang et al, 2000;Zong et al, 2000). We hypothesized, therefore, that the Stat3 phosphorylation and activation in ovarian cancer cell lines may be due to the constitutive activation of the upstream signals translated by JAKs or through aberrancies in the JAKs themselves.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells

et al. 2001

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Signal transducers and activators of transcription (STATs) are transcription factors activated in response to cytokines and growth factors. Constitutively active Stat3 has been shown to mediate oncogenic transformation in cultured cells and induce tumor formation in mice. An increasing number of tumor-derived cell lines as well as samples from human cancer have been reported to express constitutively active Stat3 protein. We previously demonstrated that ovarian cancer cell lines express high levels of constitutively active Stat3. In this study, we show that inhibition of the Stat3 signaling pathway using the Janus Kinase-selective inhibitor, AG490, and a dominant negative Stat3 (Stat3b) signi®cantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ovarian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-x L . Further, AG490 induced signi®cant apoptosis in ovarian and breast cancer cell lines expressing high levels of constitutively active Stat3 but had a less profound e ect on normal cells lacking constitutively active Stat3. AG490 also enhanced apoptosis induced by cisplatin in ovarian cancer cells. These results suggest that inhibition of Stat3 signaling may provide a potential therapeutic approach for treating ovarian and breast cancers. Oncogene (2001) 20, 7925 ± 7934.

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“…For example, Src could provide a docking site for JAKs or STATs during PDGF-stimulated STAT tyrosine phosphorylation. Indeed, STAT3 and JAK1 are constitutively tyrosine phosphorylated and complexed with Src in cells transformed by activated, mutant Src (Cao et al, 1996;Campbell et al, 1997). To test for a role for Src family members in STAT activation, we have performed preliminary experiments in cell lines derived from mouse embryos that lack the Src family members Src, Fyn and Yes (Richard Klingho er, C Sachsenmaier, JA Cooper, Philippe Soriano, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

1999

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Activation of the platelet-derived growth factor (PDGF) receptor tyrosine kinase induces tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. Since the PDGF receptor also activates the Src tyrosine kinase, it is possible that Src mediates tyrosine phosphorylation of STATs in PDGFtreated cells. Consistent with a role for Src in STAT activation, we found that a PDGF receptor juxtamembrane tyrosine residue required for Src activation is necessary and su cient for activation of STATs 1 and 3. To test the Src requirement further, we made other mutations in the PDGF receptor juxtamembrane region that increased or decreased Src binding. In epithelial and ®broblast cells, PDGF activated STAT1, 3 and 6 in the absence of detectable binding and activation of Src. In addition, PDGF induced c-myc RNA expression and DNA synthesis even though Src was not detectably activated. The activation of MAP kinase and the induction of c-fos gene expression both correlated with STAT but not Src activation by the receptor. We conclude that juxtamembrane tyrosine phosphorylation is necessary for both Src tyrosine kinase and STAT activation by the bPDGF receptor, but that both processes are regulated independently by this region.

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Constitutive Activation of JAK1 in Src-transformed Cells

Cited by 98 publications

References 31 publications

Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

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