HIPK2

Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.^[5] HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors.^[6] It belongs to a family of protein kinases known as the DYRK kinases.^[7] Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3.^[8] HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.

Discovery

HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed, yielded products that interacted with transcription factors related to the NK

There is evidence to suggest that HIPKs including HIPK2 are evolutionarily conserved proteins across a wide array of species. The human sequence shares a close similarity to a sequence from the genome of Caenorhabditis elegans.^[8] HIPKs also share a close similarity with YAK1 in yeast and are in the same family as a kinase from Dictyostelium.^[7][8] Furthermore, HIPKs are able to interact with homeoproteins from other species, such as NK-1 and NK-3 in Drosophila as well as Nkx-2.5 in mice.^[8] HIPK2 can also be found in dogs,^[9] cats,^[10] sheep,^[11] and zebrafish^[12] as well as many other species.

Localization

Expression in tissues

HIPK2 is expressed in nearly all tissue types, however it is highly expressed in the heart, muscle and kidneys.

HIPK2 is found in the nucleus within structures called nuclear speckles.^[7][15] It is also associated with PML bodies, which are also structures found in the nucleus.^[16] Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic.^[17]

Structure

Gene

The HIPK2 gene contains 13

HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications.[31]^[30][32][33]

Positive

Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation. The activity of HIPK2 is increased through the action of

Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation.[17]^[31] The PEST sequence found in HIPK2 is also linked to protein degradation.^[34] HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm.^[17] In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis.^[30]

p53

Two mutations have been discovered in the speckle retention sequence, both of which are missense.^[36] 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.^[36] The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13.^[36] These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles.^[36] The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function.^[36]

Interactions

HIPK2 interacts with several other proteins:

• CREB binding protein^[37]
• p53^[27]
• p300^[32]
• SKI protein^[38]
• TP53INP1^[39]
• ATM kinase^[17]
• PIN1^[33]
• HMGA1^[17]
• SIAH1^[17]
• WSB1^[17]
• caspase 6^[35]
• Tachykinin receptor 3^[8]
• Mdm2^[34]
• CtBP^[29]

Clinical significance

Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia,^[36] myelodysplastic syndrome^[36] through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2.^[40] Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis^[41] and cardiovascular disease.^[42]

References