Seven members of the signal transducer and transcriptional activator (STAT) protein family are transcription factors that are activated in response to downstream signaling by growth factors and cytokines. STATs are dysregulated in a wide range of cancer types. Although the gene encoding STAT is rarely mutated in cancer, constitutive phosphorylation and hence STAT activation, particularly STAT3, is a common change in cancer. STAT3 and STAT5 are thought to play a major role in tumorigenesis in tumor cells and tumor microenvironment (TME), while STAT1 has been described as a tumor suppressor (although recent publications have also revealed the tumorigenic function of STAT1).
Classification of STAT family
The Signal Transduction and Transcription Activator (STAT) family contains seven structurally similar proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6) that act as signaling proteins and transcription factors. STAT5A and STAT5B are encoded by two different genes that produce highly homologous proteins. Although STAT5A and STAT5B are different proteins with overlapping but non-redundant functions, they are commonly referred to as STAT5. Each STAT protein consists of six functional conserved domains, including the SH2 domain and the C-terminal transactivation domain (TAD), which can be phosphorylated on a conserved tyrosine residue (Tyr705 in STAT3). Tyrosine phosphorylation of STAT usually occurs downstream of cytokines and growth factor receptors. Phosphorylation of STAT proteins leads to STAT dimerization and translocation into the nucleus, where STAT dimers can activate or inhibit transcription. Thus, phosphorylation of STAT links growth factor and cytokine signaling to gene expression. Tyrosine phosphorylation of the TAD domain is the most well characterized post-translational modification of the STAT protein.
STAT Function in the Nucleus
The STAT protein dimer is transported into the nucleus by the input protein. Once introduced, STAT proteins can promote or downregulate gene expression, usually by co-suppressors with coactivators and transcription. Therefore, STAT target gene expression can be formed not only by the expression, phosphorylation and nuclear translocation of the STAT protein itself, but also by the formation of transcriptional co-regulatory factors. It is worth noting that although tyrosine phosphorylation of STAT protein plays a major role in STAT function, dimerization can occur independently of tyrosine phosphorylation, and unphosphorylated STAT protein has also been shown to enter the nucleus. And activate gene transcription, usually in cooperation with other proteins. Transcription factor. For example, unphosphorylated STAT3 can cooperate with nuclear factor kappa B (NF-κB) to promote transcription of oncogene MET.
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3. Dupuis S.; et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nature Genetics, 2012, 33(3): 388–391.