regulates HIPK2 by activating the ubiquitin ligase mdm2. An interaction of mdm2 and HIPK2 leads to the ubiquitination and eventual degradation of HIPK2. Mutations Two mutations have been discovered in the speckle retention sequence, both of which are missense. One of which was named R868W, meaning that at residue 868 where the wild type amino acid sequence would have contained an arginine residue, it now contains a tryptophan residue. The other mutation was named N958I, meaning that at residue 958 where the wild type amino acid sequence would have contained an asparagine residue, it now contains an isoleucine residue. The R868W mutation is the result of cytosine to thymine point mutation and the N985I mutation resulted from an adenine to thymine point mutation. The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13. These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles. The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function. Interactions HIPK2 interacts with several other proteins: CREB binding protein p53 p300 SKI protein TP53INP1 ATM kinase PIN1 HMGA1 SIAH1 WSB1 caspase 6 Tachykinin receptor 3 Mdm2 CtBP Clinical significance Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia, myelodysplastic syndrome through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2. Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis and cardiovascular disease. References Further reading External links https://www.proteinatlas.org/ENSG00000064393-HIPK2/tissue#gene_information