STAT

From Ganfyd

Activated STAT functions as either homodimers or heterodimers. Some heterodimers can be inactive which is possibly the case in some forms of Hyper-IgE syndrome.

• STAT1 (signal transducer and activator of transcription 1)
  • Coded at 2q32.2.
  • Two alternatively spliced transcript variants encoding distinct isoforms.
• STAT2 (signal transducer and activator of transcription 2)
  • Coded at 12q13.2
  • Interferon (IFN) causes it to complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G). The complex acts as a transactivator, but lacks the ability to bind DNA directly.
  • Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with STAT2. This seems to be involved in the process whereby adenoviruses block interferon alpha response.
• STAT3 (signal transducer and activator of transcription 3, acute-phase response factor)
  • Coded at 17q21.31
  • Three isoforms
  • Regulates cell growth and apoptosis.
  • RAC1, a small GTPase binds and regulates it.
  • PIAS3 is a specific inhibitor
  • Is a small ubiquitin-like modifier (SUMO)-E3 ligase which binds to several transcription factors
  • Has several spliced variants
  • Causative role in much malignancy
    • 40% of patients with large granular lymphocytic leukaemia have a STAT3 mutation in active clone
  • Mutations affecting its DNA binding ability cause hyper-IgE syndrome
• STAT4 (signal transducer and activator of transcription 4)
  • Coded for at 2q32.2-q32.3
  • Mediates responses to interleukin-12 in lymphocytes
  • Regulates differentiation of T helper cells.
  • Genetic polymorphisms associated with SLE
• STAT5a (signal transducer and activator of transcription 5a)
  • Coded for at 17q11.2
  • Activation in multiple myeloma and lymphoma associated with TEL/JAK2 gene fusion is essential for tumorigenesis
  • May have a role in breast development
  • Is usually antiapoptotic
• STAT5b (signal transducer and activator of transcription 5b, STAT5)
  • Coded for at 17q11.2
  • Deficiency causes insensitivity to growth hormone
  • Wide involvement including in TCR signaling, apoptosis, breast development, and liver gene expression based on sex.
  • Fusion of its gene with retinoic acid receptor-alpha (RARA) gene causes some acute promyelocytic leukaemias.
• STAT6 (signal transducer and activator of transcription 6)
  • Coded for at 12q13
  • Key in interleukin-4 response.
  • Induces BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4.
  • Mutations are associated with asthma and atrophy

Leptin may modulate STATs 3, 5, and 6 and its receptor is similar to JAK3 being a gp130 cytokine receptor family member.