STAT3beta, a distinct isoform from STAT3

STAT3 beta is an isoform of STAT3 (signal transducer and activator of transcription 3) that differs from the STAT3 alpha isoform by the replacement of the C-terminal 55 amino acid residues with 7 specific residues. The constitutive activation of STAT3 alpha plays a pivotal role in the activation of oncogenic pathways, such as cell proliferation, maturation and survival, while STAT3 beta is often referred to as a dominant-negative regulator of cancer. STAT3 beta reveals a spongy cushion effect through its cooperation with STAT3 alpha or forms a ternary complex with other co-activators. Especially in tumour cells, relatively high levels of STAT3 beta lead to some favourable changes. However, there are still many mechanisms that have not been clearly explained in contrast to STAT3 alpha, such as STAT3 beta nuclear retention, more stable heterodimers and the prolonged Y705 phosphorylation. In addition to its transcriptional activities, STAT3 beta may also function in the cytosol with respect to the mitochondria, cytoskeleton rearrangements and metastasis of cancer cells. In this review, we summarize the mechanisms that underlie the unique roles of STAT3 beta combined with total STAT3 to enlighten and draw the attention of researchers studying STAT3 and discuss some interesting questions that warrant answers.