The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Abstract

STAT3 is an important transcription factor that regulates cell growth and proliferation by regulating gene transcription of a plethora of genes. This protein also has many roles in cancer progression and several tumors such as prostate, lung, breast, and intestine cancers that are characterized by strong STAT3-dependent transcriptional activity. This protein is post-translationally modified in different ways according to cellular context and stimulus, and the same post-translational modification can have opposite effects in different cellular models. In this review, we describe the studies performed on the main modifications affecting the activity of STAT3: phosphorylation of tyrosine 705 and serine 727; acetylation of lysine 49, 87, 601, 615, 631, 685, 707, and 709; and methylation of lysine 49, 140, and 180. The extensive results obtained by different studies demonstrate that post-translational modifications drastically change STAT3 activities and that we need further analysis to properly elucidate all the functions of this multifaceted transcription factor.

Keywords: STAT3; acetylation; methylation; phosphorylation; post-translational modifications.

Figure 1

Schematic structure of STAT3 protein: STAT3 has a N-terminus domain (NTD), a coil-coiled domain (CDD), a DNA binding domain (DBD), a linker region (LD), a SH2 domain, and a transactivation domain (TAD) in the C-terminal portion of the protein. Phosphorylation, acetylation, and methylation sites are highlighted. Created with BioRender.com.

Figure 2

Schematic representation of IL-6/JAK/STAT3 pathway: IL-6 family members recognize their cognate transmembrane receptors and transmembrane proteins associated with the receptors trigger the activation of JAKs. Activated JAKs phosphorylate Y705 of STAT3 and pSTAT3 Y705 migrates to the nucleus. In the nucleus, STAT3 can be acetylated by p300/CBP and methylated by SET9 or by EZH2. HDAC and LSD1 inhibit AcSTAT3 and MeSTAT3, respectively. The Ras/Raf/MEK/ERK pathway determines S727 phosphorylation. Y705 and S727 are both required for mitochondrial functions of STAT3. Alternatively, unphosphorylated STAT3 (U-STAT3) can also regulate specific nuclear targets. Created with BioRender.com.

Figure 3

Main constructs used to investigate STAT3 phosphorylation. Created with BioRender.com.

Figure 4

Main constructs used to investigate STAT3 acetylation. Created with BioRender.com.

Figure 5

Main constructs used to investigate STAT3 methylations. Created with BioRender.com.