STAT5A Target Analysis Report Summary
About the Target
Based on the provided context, the key viewpoints about STAT5A (synonymous with STAT5) are as follows:
STAT5 Activation: STAT5 activation is a two-step process. First, the STAT5 monomer docks to a phospho-tyrosyl moiety of the tyrosine kinase-receptor complex, leading to phosphorylation of the Y694/699 residue of STAT5A and STAT5B by a tyrosine kinase [1]. This docking is mediated by the SH2 domain of STAT5 and is necessary for STAT5 phosphorylation [1].
Dimerization and Transcriptional Activity: After phosphorylation, the SH2 domain of a phosphorylated STAT5 monomer binds the phosphorylated Y694/699 residue of the partner STAT5 to form a transcriptionally active parallel dimer [1]. This dimer then translocates to the nucleus to regulate transcription [1].
STAT5 Inhibition: The proposed inhibitor IST5-002 (IST5) targets the SH2 domain of STAT5 monomer [1]. It blocks the binding of phosphorylated STAT5 monomer to the pY694/699 residues of the partner STAT5 monomer, preventing dimerization [1]. Additionally, IST5 inhibits the transient docking of the SH2 domain to the tyrosine kinase-receptor complex, leading to suppression of STAT5 phosphorylation and activation [1].
Chromatin Regulation: STAT5 is involved in chromatin compaction through interaction with heterochromatin protein 1alpha (HP1alpha) [2]. It also interacts with CTCF, influencing each other's transcriptional activity [2]. Moreover, promoter-bound transcription factors like STAT5 can be modified by histone-modifying enzymes, affecting target gene transcription [3].
Dasatinib Effects: Dasatinib inhibits the Src-mediated STAT phosphorylation pathway, while the JAK-activation pathway compensates and allows STAT5 phosphorylation [4]. Hence, prolonged exposure to IL-7 and IL-15 cytokines can still induce STAT5 phosphorylation even in the presence of Dasatinib [4].
Epo-R Signaling: STAT5 is activated through the Jak/STAT pathway upon Epo-R signaling [5]. It subsequently induces transcription of proproliferation and antiapoptotic signals [5]. Negative-feedback loops, such as the expression of SOCS proteins and involvement of phosphatases, are also activated to diminish signaling [5].
Overall, STAT5 plays a crucial role in cellular signaling, transcriptional regulation, and chromatin compaction, and its activation and dimerization are tightly regulated. Additionally, targeting the SH2 domain of STAT5 can inhibit its activation and dimerization, which may have potential therapeutic implications.
Based on the provided context information, here are some key viewpoints about STAT5A:
In compliant environments, PRL/PRLR preferentially activates JAK2/STAT5, resulting in physiological PRL actions. However, in stiff environments, PRL/PRLR preferentially activates SFKs and FAK, leading to pro-tumor progressive signals and outcomes [6].
Low shear stress (LowSS) represses the expression of Nesprin2 and LaminA, which affects the activation of transcription factors (AP-2, TFIID, Stat-1, Stat-3, Stat-5, Stat-6), thereby influencing the proliferation and apoptosis of endothelial cells (ECs) [7].
The isoforms of Bcr-Abl (p210 and p190) show differences in their interactors and phosphorylated proteins. p210 exhibits stronger association with the Sts1 phosphatase and higher activation of Stat5 transcription factor, as well as Erk1/2 and Fyn/Lck kinases. On the other hand, p190 shows stronger association with the AP2 complex, clathrin, Dok1 adaptor, and Lyn kinase [8].
In T-cell acute lymphoblastic leukemia (T-ALL) cells, STAT5 is required for IL-7-mediated cell cycle progression and viability, while Bcl-2 is upregulated by IL-7 via the PI3K/Akt/mTOR pathway. However, in normal T-cells, STAT5 appears to transcriptionally activate Bcl-2 and upregulate viability, while PI3K/Akt/mTOR pathway is involved in cell cycle progression [9].
In acute myeloid leukemia (AML) cells, FLT3-ITD is retained in the Golgi apparatus, where it activates kinases (AKT and ERK) in the perinuclear Golgi region. Additionally, FLT3-ITD activates STAT5 in the endoplasmic reticulum (ER), where it is synthesized [10].
These findings suggest that STAT5A plays a significant role in various cellular processes, including physiological actions stimulated by PRL, proliferation and apoptosis of ECs, differential signaling networks in Bcr-Abl isoforms, viability regulation in T-ALL cells, and intracellular signaling in AML cells.
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Note: If you are interested in the full version of this target analysis report, or if you'd like to learn how our AI-powered BDE-Chem can design therapeutic molecules to interact with the STAT5A target at a cost 90% lower than traditional approaches, please feel free to contact us at BD@silexon.ai.
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