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Biochemical aspects of FOXP2 SUMOylation C-terminal carboxyl groups of SUMOS appear to interact with the amino group of FOXP2 via an isopeptide linkage. This amino group of the FOXP2 protein has a lysine side chain with the ΨKX (where Ψ is a hydrophobic amino acid and X is any other amino acid) consensus sequence . The SP-RING domain of the SUMO helps its FOXP2 recognition. N-terminal FOXP2 region contain some of the most important determinants of PIAS binding. These are K674 with PE motif and other residues, e.g. K285, K417 and K560 of the VE sequence. All of these residues are conserved in FOXP2. In this experiment a for SUMO conjugation required Arginine was removed and the SUMOLlyation did not happened. This showed that the K674 is the most important determinant for the SUMO1, SUMO2 and SUMO3 modifications. The mutants assay showed normal dimerization ability in the BRET, so the researchers concluded that the suppressed SUMOylation does not affect the FOXP2 ability to form homodimers or to interact with the CtBP129 co-repressor. This is because FOXP2 dimerization occurs with the help of the leucine zipper domain. However, the leucine zipper domain is not located near the SUMOylation site. This region includes domains that are highly conserved in FOXP1 and FOXP4. These domains serve as recognition sites for the autism-relevant transcription factor TBR1. This area is probably responsible for several protein-protein interactions. (Deriziotis et al., 2014) SUMOilization in FOXP1 / 4 genes Three SUMO proteomic studies of human cell lines identified FOXP1 and FOXP4 as substrates for SUMOilination. (Golebiowski et al., 2009; Tatham et al., 2011; Wen et al., 2014) FOXP1 and FOXP4 contain the SUMOylation relevant DNA motif that is identical to the corresponding FOXP2 motif of the surrounding PE sequence. In BRET study, FOXP1 also showed interactions with PIAS1, PIAS2, and PIAS4, but in contrast to FOXP2, FOXP1 showed little or no interaction with PIAS3. The FOXP1 also showed interactions with all three SUMOs. Probably FOXP1 is also Sumoylated by SUMO1, SUMO2 and SUMO3 at a location, like the K636 site of FOXP2. So, members of the PIAS family are act different in FOXP1 and FOXP2 SUMOylation.
Influence of FOXP2 SUMOlyatin on various diseases It is known that not only FOXP1 and FOXP4 transcription factor TBR1 and co-repressor CtBP1 interact with FOXP2. (Deriziotis et al., 2014; Li et al., 2004; Meulmeester and Melchior, 2008; Rytinki et al., 2009). So by speech and language disorders afflicted family showed a strongly reduced FOXP2 SUMOylation. SUMOylation appears to occur in thousands of nuclear proteins in all cell types at different stages of development (Meulmeester and Melchior, 2008; Gwizdek et al., 2013). According to Bacon and Rappold (2012) and Zhao et al. (2014) SUMO influences dendritic and synaptic morphogenesis by modifying neuronal proteins. Different PIASs may be involved in SUMOylation of various FOXPs and may affect the modification of neuronal circuits. In addition, they support the neuronal plasticity, but it is unclear whether a change in SUMOylation level during brain development leads to functional impairment. It has been demonstrated that PIAS1 knockout causes perinatal lethality in mice. (Loriol et al., 2012; Hasegawa et al., 2014) The study of Estruch et al. (2016) revealed that the four PIAS were continuously expressed but the PIAS1 and PIAS3 were expressed at the same extent in all tissues tested while the PIAS2 and PIAS4 were expressed primarily in testis. Studies of Turner et al. (2013), Adegbola et al. (2015), Nazaryan et al. (2014), Utine et al. (2014) and the fact that the FOXP2 plays a role in neuronal migration, neurite growth, in synaptic plasticity and in the language-related brain circuits (Garcia-Caleroet al., 2015; Tsui et al., 2013; Verne et al., 2011; Groszer et al., 2008) allowed another hypothesis about the cause of speech disorders in the KE family. All members of the by the speech disorder afflicted KE family had a heterozygous R553H mutation in the DNA-binding domain. In twenty other similar cases a missense mutation (R553H) in the FOX DNA binding domain that makes DNA binding and transcriptional repression by FOXP2 impossible was found. Nonsense and frameshift mutations, as well as chromosomal rearrangements were accompanied by similar disabilities. In contrast to the partially compensated interactions between the SUMOS and the K674R mutant the BRET assay showed an almost complete loss of the interactions between the SUMOS and R553H mutant compared to the wild type. The most important SUMOylation site stayed intact in the R553H mutants so the reduction of SUMOylation may base on reduced or absent interaction between the mutant and the PIASs or UBC9. In contrast to the K674R mutants which interact with PIAS but cannot be SUMOylated, the R553H mutants had reduced interaction with PIAS, which can be compensated by PIAS overexpression or by a fusion with UBC9. The R553H mutation also led to partial mislocalization and increased protein aggregation. The R553H mutation may lead to a conformational change that blocks the PIAS binding site. Alternatively, the loss of DNA binding capacity resulting from the R553H mutation and / or destabilization of the protein domain may trigger FOX interactions with other cellular proteins that interfere with PIAS binding. It seems to be useful to investigate the extent of the FOXP2 SUMOylation and the FOXP2-PIAS interactions in different issues and possibly further regulatory mechanisms of aging related neurodegeneration.
FOXP2 regulates proto-oncogenes p21WAF1 / RAS 1, BCL-2, HES1 and other cancer-relevant genes. Gascoyne et al. (2015) demonstrated in „The forkhead transcription factor FOXP2 is required for regulation of p21WAF1 / CIP1 in 143B osteosarcoma cell growth arrest“ with the help of human osteosarcoma cell cultures and normal human osteoblasts that the forkhead transcription factor FOXP2 regulates proto-oncogenes p21WAF1 and CIP1. These proto-oncogenes are required for osteosarcoma cell growth arrest. lncRNA-p21 influences cell proliferation and carcinogenesis via vβ-catenin and JunB. The lncRNA HULC is highly expressed in age related colorectal carcinomas and UCA1 is highly expressed in bladder transitional cell carcinoma by modulating p27 level and can affect cellular senescence.(Parket al., 2011; Smith-Vikos and Slack,