Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T (original) (raw)
Related papers
The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
Oncotarget, 2016
The role of STAT1 and STAT3 for colorectal carcinoma (CRC) development and progression is controversial. We evaluated 414 CRC patient samples on tissue microarrays for differential expression of STAT1 and STAT3 protein levels and correlated ratios with clinical parameters. Concomitant absence of nuclear STAT1 and STAT3 expression was associated with significantly reduced median survival by ≥33 months (p=0.003). To gain insight into underlying mechanisms, we generated four CRC cell lines with STAT3 knockdown. The cell lines harbor different known mutational drivers and were xenografted into SCID mice to analyze the influence of STAT3 on their tumor growth behavior. Experimental downregulation of STAT3 expression had differential, cell-line specific effects on STAT1 expression levels. STAT1 consistently showed nuclear localization irrespective of its tyrosine phosphorylation status. Two characteristic STAT1/3 expression patterns with opposite growth behavior could be distinguished: cell lines with a low STAT1/high STAT3 ratio showed faster tumor growth in xenografts. In contrast, xenografts of cell lines showing high STAT1 and low STAT3 levels grew slower. Importantly, these ratios reflected clinical outcome in CRC patients as well. We conclude that the ratio of STAT1 to STAT3 expression is a key determinant of CRC progression and that STAT1 counteracts pro-tumorigenic STAT3 signaling. Thus, we suggest that the STAT3/STAT1 ratios are better clinical predictors in CRC as compared to STAT3 or STAT1 levels alone.
Cross-talk between Phospho-STAT3 and PLC 1 Plays a Critical Role in Colorectal Tumorigenesis
Molecular Cancer Research, 2011
Hyper-phosphorylation at the Y705 residue of signal transducer and activator of transcription 3 (STAT3) is implicated in tumorigenesis of leukemia and some solid tumors. However, its role in the development of colorectal cancer (CRC) is not well defined. To rigorously test the impact of this phosphorylation on colorectal tumorigenesis, we engineered a STAT3 Y705F knock-in to interrupt STAT3 activity in HCT116 and RKO CRC cells. These STAT3 Y705F mutant cells fail to respond to cytokine stimulation and grow slower than parental cells. These mutant cells are also greatly diminished in their abilities to form colonies in culture, to exhibit anchorage-independent growth in soft agar, and to grow as xenografts in nude mice. These observations strongly support the premise that STAT3 Y705 phosphorylation is crucial in colorectal tumorigenesis. Although it is generally believed that STAT3 functions as a transcription factor, recent studies indicate that transcription-independent functions of STAT3 also play an important role in tumorigenesis. We show here that wild-type STAT3, but not STAT3 Y705F mutant protein, associates with PLCγ1. PLCγ1 is a central signal transducer of growth factor and cytokine signaling pathways that are involved in tumorigenesis. In STAT3 Y705F mutant CRC cells, PLCγ1 activity is reduced. Moreover, over-expression of a constitutively active form of PLC γ1 rescues the transformation defect of STAT3 Y705F mutant cells. In aggregate, our study identifies previously unknown cross-talk between STAT3 and the PLCγ signaling pathways that may play a critical role in colorectal tumorigenesis.
Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein
… and Cell Biology, 2009
Signal transducer and activator of transcription protein 3 (STAT3) is a latent cytosolic transcription factor that is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutively activated STAT3 protein activity is routinely observed in human cancers, promoting uncontrolled cell proliferation and suppressing apoptosis. Until relatively recently, inhibition of STAT3 transcriptional activity was achieved indirectly via suppression of upstream kinase activators and extracellular cytokine and (or) growth factor stimuli. However, activated STAT3 forms transcriptionally functional STAT3-STAT3 dimers, providing a valid juncture for targeted downstream molecular inhibition. STAT3's prominent role in cancer has seen a decade of innovative and novel approaches to targeting constitutively active STAT3 protein-protein complexes. This mini-review outlines the progress made towards identifying molecular agents capable of silencing aberrant STAT3 signalling through the disruption of STAT3 complexation events.
Neoplasia, 2005
Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6 -driven proliferation. Blockade of STAT3 activation in CRCderived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth. Neoplasia (2005) 7, 545 -555
STAT proteins: from normal control of cellular events to tumorigenesis
Journal of cellular physiology, 2003
Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in ...
European Journal of Cancer, 2006
The Janus family of tyrosine kinases (JAK) and the signal transducer and activator of transcription (STAT) family are critical components of diverse signal transduction pathways that are actively involved in cellular survival, proliferation, differentiation, and apoptosis. Accumulating evidence also supports a role for STAT proteins in oncogenesis. STATs transduce signals emanating from the large haematopoietin subfamily of cytokines, including the interferon, the gp130, the cC and the single chain families of receptors. 1 STATs can also be activated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), colony stimulating factor-1 receptor (CSF-1R), and platelet derived growth factor receptor (PDGFR). Several members of the G-protein-coupled receptors have also been shown to signal through STATs. The binding of a cytokine to its receptor induces the receptor's oligomerisation which in turn triggers the activation of JAKs by either auto-or transphosphorylation. There are four members of the JAK family in mammals, Jak1, Jak2, Jak3 and Tyk2. Jak1, Jak2 and Tyk2 are expressed ubiquitously, whereas the expression of Jak3 is restricted to cells of the myeloid and lymphoid lineages. The activated JAKs phosphorylate the receptors on specific tyrosine sites, which generate docking sites for the recruitment of cytoplasmic monomeric STAT proteins via their SH2 (Src homology 2) domains. Subsequently, the recruited STATs are phosphorylated by activated JAKs and dimerise via reciprocal phosphotyrosine-SH2 domain interactions. STAT 3 is also regulated by phosphorylation on its serine residue 727. 4 This phosphorylation can be inhibitory and the kinase responsible is not clearly identified. The dimers translocate to the nucleus, where they bind to specific DNA response elements which regulate gene expression. 5 STAT signalling is thought to be terminated by dephosphorylation through nuclear tyrosine phosphatases and/or through proteolytic degradation. Moreover, few phosphatases such as SHP1 are known to dephosphorylate JAK/STAT proteins and SHP1 remains one of the phosphatases identified which downregulates STAT3. 6 Seven members of the STAT family encoded in distinct genes have been identified in mammalian cells: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT 6. STAT1 and STAT3 exhibit two isoforms each resulting from alternative splicing 5 whereas STAT5a and STAT5b are encoded by distinct genes. STAT proteins have a well-defined structure including a DNA-binding domain, a conserved NH 2 -terminal domain, a COOH-terminal transactivation domain, and an SH2 domain. Concerning STAT signalling pathway, it is modulated by interacted molecules: among them, the SOCS protein and PIAS protein have been described to play a crucial role in the regulation of STAT signalling pathway. 7 The SOCS protein belongs to a group of cytokine-inducible genes that have been shown to inhibit STAT signalling by binding to JAKS. Some of the SOCS protein can also be regulated by STATS themselves, providing that STAT can regulate its own phosphorylation status. 8 For instance, SOCS-3 has been demonstrated as a negative regulator of STAT3 and STAT5 activation. As for PIAS proteins, they generally play a role by decreasing DNA activation via STAT DNA-binding activity. The overexpression of PIAS1 and PIAS3 represents a specific nuclear inhibition of STAT1 and STAT3 and by consequence prevents the activation of STAT-dependent gene transcription.
Signal Transducer and Activator of Transcription 3 (STAT 3) Gene Polymorphism and Gastric Carcinoma
Gastroenterology, 2011
Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood. We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/ paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD. signal transduction | cytokines | preclinical
Scientific Reports
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor mainly activated by phosphorylation in either tyrosine 705 (Y705) or serine 727 (S727) residues that regulates essential processes such as cell differentiation, apoptosis inhibition, or cell survival. Aberrant activation of STAT3 has been related to development of nearly 50% of human cancers including clear cell renal cell carcinoma (ccRCC). In fact, phosho-S727 (pS727) levels correlate with overall survival of ccRCC patients. With the aim to elucidate the contribution of STAT3 phosphorylation in ccRCC development and progression, we have generated human-derived ccRCC cell lines carrying STAT3 Y705 and S727 phosphomutants. Our data show that the phosphomimetic substitution Ser727Asp facilitates a pro-tumoral phenotype in vitro, in a Y705-phosphorylation-independent manner. Moreover, we describe that STAT3 phosphorylation state determines the expression of different subsets of target genes associ...
Oncogene, 2014
The signal transducer and activator of transcription 3 (STAT3) can be activated by the tyrosine kinase domain of the chimeric protein nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), and has a pivotal role in mediating NPM/ALK-related malignant cell transformation. Although the role of STAT3 and wild-type NPM in oncogenesis has been extensively investigated, the relationship between both molecules in cancer remains poorly understood. In the present study, we first demonstrate that STAT3 phosphorylation at tyrosine 705 is accompanied by a concomitant increase in the expression level of NPM. Nuclear co-translocation of phosphorylated STAT3 with NPM can be triggered by interferon-alpha (IFN-α) stimulation of Jurkat cells and phosphorylated STAT3 co-localizes with NPM in cancer cells showing constitutive STAT3 activation. We further demonstrate that STAT3 phosphorylation can transcriptionally mediate NPM upregulation in IFN-α-stimulated Jurkat cells and is responsible for maintaining its expression in cancer cells showing constitutive STAT3 activation. Inhibition of STAT3 phosphorylation or knockdown of NPM expression abrogates their simultaneous transnuclear movements. Finally, we found evidence for a physical interaction between NPM and STAT3 in conditions of STAT3 activation. In conclusion, NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. These observations might open novel opportunities for targeting the STAT3 pathway in cancer.