STAT5B - dismech genes

Normal function · from ai-gene-review (P51692, commit 79fe13b38970) · AI-generated, not KB evidence

STAT5B is a latent cytoplasmic signal transducer and sequence-specific transcription factor of the STAT family. It is composed of an N-terminal domain, a coiled-coil domain, a DNA-binding domain, a linker, an SH2 domain, and a C-terminal transactivation domain. STAT5B is activated downstream of numerous cytokine and hormone receptors: it is the principal signal transducer for growth hormone (via JAK2), is activated by the common gamma-chain cytokines IL-2, IL-7, IL-9, IL-15 and IL-21 (via JAK1/JAK3), and is also activated by prolactin, erythropoietin and thrombopoietin (via JAK2), GM-CSF/IL-3/IL-5, G-CSF, and oncostatin-M. Receptor-associated JAK kinases phosphorylate STAT5B on Tyr-699; phosphorylated STAT5B dimerizes through reciprocal SH2-phosphotyrosine interactions (and can form heterodimers with STAT5A or STAT3), translocates to the nucleus, and binds gamma-activated sequence (GAS) DNA elements to activate transcription of target genes. STAT5B drives transcriptional programs controlling postnatal growth (induction of IGF1 downstream of growth hormone), lymphocyte development and immune homeostasis (including regulatory T cells and NK cells), and erythroid/hematopoietic differentiation. Loss-of-function variants cause growth hormone insensitivity syndrome with immune dysregulation (short stature with low IGF1 and normal/elevated growth hormone), while somatic activating mutations such as the SH2-domain N642H substitution drive T-cell and NK-cell leukemias and lymphomas. STAT5B is highly similar to and largely functionally overlapping with, but non-redundant from, its paralog STAT5A.

STAT5B is a sequence-specific RNA polymerase II transcription factor that, once activated, binds gamma-activated sequence (GAS) elements in cis-regulatory regions of target genes and activates their transcription, recruiting coactivators such as CBP/p300 (via NMI) and NCOA1/SRC-1. DNA binding and transactivation are directly demonstrated by EMSA against the GHRE/GAS probe and luciferase reporter assays; DNA-binding-domain disease variants abolish both activities.

molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific · directly involved in: positive regulation of transcription by RNA polymerase II · locations: nucleus; chromatin

STAT5B is a latent cytoplasmic signal transducer for cytokine and hormone receptors that signal through the JAK-STAT pathway. Receptor-associated JAK kinases (JAK1/JAK2/JAK3) phosphorylate STAT5B on Tyr-699, which is required for its activation; this couples upstream signals (common gamma-chain cytokines IL-2/7/9/15/21, growth hormone, prolactin, erythropoietin, thrombopoietin, GM-CSF/IL-3/IL-5) to transcriptional output. This includes the growth hormone receptor signaling pathway that drives IGF1 induction, and erythropoietin-mediated signaling in erythroid precursors.

molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific · directly involved in: cell surface receptor signaling pathway via JAK-STAT; cytokine-mediated signaling pathway; growth hormone receptor signaling pathway via JAK-STAT; erythropoietin-mediated signaling pathway · locations: cytoplasm; nucleus

Upon tyrosine phosphorylation, STAT5B dimerizes through reciprocal SH2-phosphotyrosine interactions (forming homodimers, and also heterodimers with STAT5A or STAT3). Dimerization is a prerequisite for nuclear translocation and DNA binding, and is the basis for the dominant-negative action of disease variants that retain dimerization but lose nuclear import or DNA binding.

molecular function: protein homodimerization activity · directly involved in: cell surface receptor signaling pathway via JAK-STAT · locations: cytoplasm; nucleus

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Growth Hormone Insensitivity Syndrome	causative germline	mechanism: GH-IGF1 Axis Disruption; STAT5B-Dependent Regulatory T-Cell Failure subtype: STAT5B Deficiency; STAT5B Dominant-Negative scoped to subtype: STAT5B Deficiency, STAT5B Dominant-Negative
Hepatosplenic T-cell Lymphoma	somatic driver	mechanism: STAT5B Gain-of-Function Activation
STAT5B Deficiency	causative germline loss of function	mechanism: Biallelic STAT5B Loss of Function
Parvovirus B19 Infection	no genetic record	mechanism: EPO-STAT5 Signaling Pathway

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
growth hormone insensitivity with immune dysregulation 1, autosomal recessive MONDO:0100211	AR	Definitive 2025-12-16	Growth Hormone Insensitivity Syndrome causative STAT5B Deficiency causative
growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant MONDO:0100219	AD	Moderate 2026-01-20	Growth Hormone Insensitivity Syndrome causative

Mechanism modules · computed from kb/

jak_stat_pathway_activation named in the module itself
sustaining_proliferative_signaling via Hepatosplenic T-cell Lymphoma