HIPK1 (homeodomain interacting protein kinase 1)

1p13.2

1210 amino acids (aa). From N-term to C-term, contains a protein kinase domain (aa 190-518), a nucleotide binding motif (aa 196-204), a domain interacting with DAB2IP (AIP1, or AF9q34, 9q33.2) (aa 518-889), a nuclear localization signal (aa 844-847), a region interacting with TP53 (aa 885-1093), a nuclear speckle retention signal (aa 887-992), (corresponding to aa 860-967 in HIPK2), a PEST domain (enriched in proline (P), glutamate (E), serine (S), and threonine (T), expedite the degradation of proteins) (aa 892-972), SUMO interaction motifs, required for nuclear localization and kinase activity (aa 902-926), a domain interacting with DAB2IP/MAP3K5 (aa 973-1209), a histidine-rich region (aa 1086-1154), and a tyrosine-rich region (aa 1175-1209) (YH region). The lysine residues at the sumoylation motifs are the following: K25, K317, K440, K556, and K1202 (Kim et al., 1998; Li et al., 2005; Swiss-Prot).
First identified as a nuclear serine/threonine kinase. Homeodomain-interacting protein kinase. HIPK1 positively or negatively modulate signaling pathways controlling cell proliferation and/or apoptosis (review in Rinaldo et al., 2008). HIPK1 and HIPK2 act cooperatively as corepressors in the transcriptional activation of angiogenic genes, including MMP10 (11q22.2) and VEGFA (6p21.1), that are critical for the early stage of vascular development (Shang et al., 2013). HIPK1 regulates the p53 signaling pathway. PARK7 (also called DJ-1, 1p36.23), a protein also linked to the p53 signaling pathway, is able to induce HIPK1 degradation. HIPK1 directly phophorylates TP53 on its serine-15. Serine 15 phosphorylation induces a rise in CDKN1A (p21, 6p21.2) expression and cell cycle arrest (Rey et al., 2013). HIPK1 phosphorylates DAXX (6p21.32), a protein which interacts with PML (15q24.1), the organizer of nuclear bodies (Ecsedy et al., 2003), and which relocalizes from the nucleus to the cytoplasm in response to stress. During glucose deprivation, a pathway involving MAP3K5 (also called ASK1, 6q23.3), -> MAP2K4 (SEK1, 17p12) -> MAPK8 (JNK1, 10q11.22) -> HIPK1 is activated, and DAXX is relocated in the cytoplasm (Song and Lee, 2003). TNF (TNF-alpha, 6p21.33) induces desumoylation and cytoplasm translocation of HIPK1 leading to apoptosis (Li et al., 2005). HIPK1 and HIPK2 bind HOX genes homeodomains and regulate their expression, as well as PAX1 (20p11.22) and PAX3 (2q36.1) transcription (Isono et al., 2006). HIPK1 and HIPK2 phosphorylates EP300 (22q13.2) and RUNX1 (21q22.12) during embryonic development, and Hipk1/Hipk2-deficient mice show defective definitive hematopoiesis (Aikawa et al., 2006). HIPK1 phosphorylates MYB (6q23.3), a transcriptional activator essential for the establishment of haemopoiesis, and causes repression of MYB activation (Matre et al., 2009). HIPK1 interacts with DVL1 (1p36.33) and TCF3 (E2A, 19p13.3) and regulates Wnt/b-catenin target genes during early embryonic development (Louie et al., 2009). HIPK1 is highly overexpressed in colorectal carcinomas compared with healthy mucosa. The highest peak of HIPK1 expression occurred at early stages and decreased in latter stages. HIPK1 appeared to be induced as a defense mechanism to fight against intern deregulations and stressful conditions, rather than produced by the cancer cells as an indispensable factor for tumor evolution (Rey et al., 2013). HIPK1 is expressed only in invasive breast cancer cells with three different subcellular localization, associated with different tumor histopathologic characteristics (Park et al., 2012).

PAX5 (paired box gene 5)

9p13.2

391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304-359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011).