Disease relevance of STAT5A

• Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin beta 1 (HRG)-stimulated cells and both proteins bind to the endogenous beta-casein promoter in T47D breast cancer cells [1].
• Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages [2].
• We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway [2].
• Activation of the Jak2-Stat5 signaling pathway in Nb2 lymphoma cells by an anti-apoptotic agent, aurintricarboxylic acid [3].
• We review these various defects with an emphasis on the GH-activated JAK2-STAT5 pathway, since this pathway is essential for normal body growth and there has been recent progress in our understanding of the perturbations that occur in uremia [4].
• We also found that persistently phosphorylated Stat5 in primary cells from patients with myeloid leukemias has a cytoplasmic localization [5].

High impact information on STAT5A

• Stat5 forms a complex with the glucocorticoid receptor which binds to DNA independently of the GRE [6].
• Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter [7].
• Expression of the protein tyrosine kinase Lck, a key signaling protein in the TCR complex, activated DNA binding of transfected STAT5A and STAT5B to specific STAT inducible elements [8].
• STAT5 became immediately and transiently phosphorylated on tyrosine 694 in response to TCR stimulation [8].
• Inhibition of STAT5 function by expression of a dominant negative mutant STAT5 reduced antigen-stimulated proliferation of T cells [8].

Chemical compound and disease context of STAT5A

• Based on these findings, we suggest that the Cas/c-Src/EGFR/STAT5 signaling axis is a major regulator of tamoxifen-resistant breast cancer cell growth and survival [9].
• Functional data show that progestin pretreatment of breast cancer cells enhances the ability of prolactin to stimulate the transcriptional activity of Stat5 on a beta-casein promoter [10].
• Naturally occurring dominant-negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells [11].
• Experimental Design: In this study we have separately determined activation of STAT1, STAT3, and STAT5 by measuring their DNA binding activity and tyrosine phosphorylation in breast cancer tissue samples [12].
• Our data demonstrate that hypoxia (2% O(2)) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11) [13].

Biological context of STAT5A

• IL-3 treatment increases JAK2 activation and STAT5A and STAT5B tyrosine and serine phosphorylation and leads to cell cycle progression in adherent cells [14].
• The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone [1].
• Consistently, overexpression of a constitutive active STAT5A leads to anchorage-independent cell cycle progression [14].
• STAT5A is a molecular regulator of proliferation, differentiation, and apoptosis in lymphohematopoietic cells [15].
• Enhanced erythropoiesis and decreased myelopoiesis were noted together with strong activation of STAT5A [16].

Anatomical context of STAT5A

• To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates beta-casein promoter activity [1].
• In BCR-Abl transformed K562 cells, STAT5A and 5B are constitutively phosphorylated on tyrosine and are transcriptionally active [17].
• Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes [18].
• Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A [18].
• We have reported previously that expression of STAT5B, but not STAT5A, could enhance the transforming potential of v-src and induces cell cycle progression and motility in fibroblasts [19].

Associations of STAT5A with chemical compounds

• Therefore, these data provide strong evidence that integrin-dependent STAT5A activation controls IL-3-mediated proliferation [14].
• Substitution of these amino acids demonstrated that a glycine residue at position 433 in STAT5B and a glutamic residue at a similar position in STAT5A determined the DNA binding specificity [20].
• The addition of the oligopeptide containing phosphotyrosine 694 in STAT5A impaired the association between GST-CrkL-SH2 and STAT5 [21].
• Moreover, the PGE2-enhancing effect was independent of STAT5 serine phosphorylation [22].
• In addition, PGE2 did not affect STAT5 serine phosphorylation [22].

Physical interactions of STAT5A

• DNA-STAT complexes were detected in all Bcr/Abl-transformed cell lines and they were supershifted by antibodies against STAT1 and STAT5 [23].
• Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity (K(d) = 44 nm), as determined by surface plasmon resonance using a BIAcore biosensor system [15].
• Activation of the Stat proteins was also detected by EMSA which revealed complex formation on the Stat3 DNA-binding element and on a Stat5 binding site [24].
• SMRT binds to both STAT5A and 5B, and strongly repressed STAT5-dependent transcription in vitro [25].
• The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways [26].

Enzymatic interactions of STAT5A

• MGF-Stat5 can be phosphorylated and activated in its DNA binding activity by Jak2 [27].
• Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo [15].
• Because Stat5 phosphorylation following cytokine stimulation is generally mediated by Jaks, the lack of Jak activation after TSLP treatment suggested the possibility that tyrosine-phosphorylated Stat5 may be nonfunctional [28].
• On the other hand, the 92-kDa STAT5 was tyrosine phosphorylated within 1 min of GM-CSF treatment and this was maintained for at least 30 min [29].
• STAT5 was a major component of this DNA-binding complex, and STAT5 was tyrosine phosphorylated in response to TPO [30].

Regulatory relationships of STAT5A

• In summary, these studies demonstrate that PGE2 enhancement of EPO-induced STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway [22].
• BTK was also capable of tyrosine-phosphorylating ectopically expressed recombinant STAT5A on Tyr(694) both in vitro and in vivo in a Janus kinase 3-independent fashion [15].
• Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the beta-casein promoter [31].
• The JAK inhibitor AG-490 blocked cytokine-induced STAT 5 phosphorylation and proliferation of M-07e cells in a dose-dependent manner [32].
• PRL also induced phosphorylation of Stat-5 in PBMC and Stat-1 in granulocytes [33].

Other interactions of STAT5A

• Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21(waf) expression and the fraction of cells in G1 [34].
• Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15 [35].
• The present study further analyzed the underlying mechanisms and demonstrated that EPO-mediated STAT5 transactivation in the erythroid AS-E2 cell line was enhanced 6-fold by PGE2 (10 microM), without affecting the STAT5 tyrosine phosphorylation or STAT5-DNA binding [22].
• Detailed analysis indicated that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as expected from the evolutionary relationships [36].
• Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation [37].

Analytical, diagnostic and therapeutic context of STAT5A

• Two distinct genes encode the closely related signal transducer and activator of transcription proteins STAT5A and STAT5B [38].
• Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR [18].
• Furthermore, gel shift analysis showed that TGF-beta1 did not prevent activated STAT4 and STAT5A from binding to DNA [39].
• In this study, DNA binding and tyrosine phosphorylation of STAT5A and STAT5B were compared with their subcellular localization determined using indirect immunofluorescence microscopy [40].
• Consequently, transduction studies were undertaken with a constitutively active mutant of STAT5A (STAT5A[1( *)6]) and here also a marked, selective expansion of transduced CD34(+) cells was noted, with a massive increase in self-renewing CAFC detectable at both 2 and 5 weeks of stromal coculture [16].

References