STAT5

STAT5 stands for Signal Transducer and Activator of Transcription 5 and is a member of the STAT family of transcription factors. In humans, two closely related genes encode STAT5A and STAT5B. STAT5 proteins are latent cytoplasmic transcription factors that become activated through cytokine receptor signaling via Janus kinases (JAKs).

Activation occurs when cytokines or hormones such as IL-2, IL-7, IL-15, growth hormone, prolactin, erythropoietin, and GM-CSF trigger receptor-associated JAKs to phosphorylate a conserved tyrosine in the STAT5 C-terminal region. This phosphorylation promotes dimerization through the SH2 domains, nuclear translocation, and transcriptional regulation of target genes involved in proliferation, differentiation, and survival.

STAT5A and STAT5B can form homodimers or heterodimers and regulate overlapping as well as distinct gene sets. They play essential roles in hematopoiesis, T cell development and function, NK cell activity, erythropoiesis, and mammary gland development. Regulation occurs through negative feedback and control by SOCS proteins, PIAS, phosphatases, and cross-talk with other signaling pathways.

Dysregulation of STAT5 signaling—such as constitutive activation or gain-of-function mutations—has been associated with hematologic malignancies including myeloproliferative neoplasms and leukemias, and can contribute to tumor cell survival. Overexpression or amplification of STAT5 pathway components has been observed in some cancers.

Therapeutically, targeting STAT5 signaling is of interest. JAK inhibitors (for example, ruxolitinib) reduce STAT5 activation, while direct STAT5 inhibitors are under development. Phospho-STAT5 serves as a pharmacodynamic biomarker of pathway activity.