An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Introns*; Alternative Splicing/*genetics ; Carrier Proteins/*chemistry ; Carrier Proteins/*metabolism ; Cytokinesis/*genetics ; Protein Serine-Threonine Kinases/*chemistry ; Protein Serine-Threonine Kinases/*metabolism; Carrier Proteins/genetics ; Codon, Terminator ; Exons ; HCT116 Cells ; HeLa Cells ; Histones/metabolism ; Humans ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Phosphorylation/genetics ; Protein Serine-Threonine Kinases/genetics ; RNA Interference ; Spastin/metabolism ; Transfection

HIPK2 is a DYRK-like kinase involved in cellular stress response pathways, development, and cell division. Two alternative splice variants of HIPK2, HIPK2-FL and HIPK2-Δe8, have been previously identified as having different protein stability but similar functional activity in the stress response. Here, we describe one additional HIPK2 splice variant with a distinct subcellular distribution and functional activity in cytokinesis. This novel splice variant lacks the last two exons and retains intron13 with a stop codon after 89 bp of the intron, generating a short isoform, HIPK2-S, that is detectable by 2D Western blots. RT-PCR analyses of tissue arrays and tumor samples show that HIPK2-FL and HIPK2-S are expressed in normal human tissues in a tissue-dependent manner and differentially expressed in human colorectal and pancreatic cancers. Gain- and loss-of-function experiments showed that in contrast to HIPK2-FL, HIPK2-S has a diffuse, non-speckled distribution and is not involved in the DNA damage response. Rather, we found that HIPK2-S, but not HIPK2-FL, localizes at the intercellular bridge, where it phosphorylates histone H2B and spastin, both required for faithful cell division. Altogether, these data show that distinct human HIPK2 splice variants are involved in distinct HIPK2-regulated functions like stress response and cytokinesis.

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Keywords: HIPK2 isoforms; abscission; alternative splicing; colorectal cancer; faithful cytokinesis; pancreatic cancer

0 (Carrier Proteins)
0 (Codon, Terminator)
0 (Histones)
0 (Isoenzymes)
EC 2.7.1.- (HIPK2 protein, human)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 3.6.4.3 (Spastin)
EC 5.6.1.1 (SPAST protein, human)

Date Created: 20200226 Date Completed: 20210219 Latest Revision: 20211204

20240829

PMC7072727

10.3390/cells9020484

32093146