SRPK1
Description
The SRPK1 (SRSF protein kinase 1) is a protein-coding gene located on chromosome 6.
Serine/arginine-Rich Splicing Factor (SRSF) protein kinase-1 SRPK1 is an enzyme that in humans is encoded by the SRPK1 gene.
== Function == This gene encodes a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. The protein localizes to the nucleus and the cytoplasm. It is thought to play a role in regulation of both constitutive and alternative splicing by regulating intracellular localization of splicing factors. A second alternatively spliced transcript variant for this gene has been described, but its full length nature has not been determined. SRPK1 enables angiogenesis, which is regulated by VEGF, which either initiates or inhibits vessel formation depending on alternative splicing.
== Medical applications == Some cancers are vascular endothelial growth factor (VEGF) dependant (for angiogenesis). SRPK1 activates (phosphorylates) VEGF splicing factor. SRPK1 inhibitors (e.g. 'SPHINX compounds' ) are under investigation as treatments for prostate cancer, acute myeloid leukemia and neovascular eye disease.
SRPK1 is a serine/arginine-rich protein-specific kinase that specifically phosphorylates its substrates at serine residues within arginine/serine-rich regions, known as RS domains. It is involved in phosphorylating SR splicing factors and regulating splicing. SRPK1 plays a central role in the splicing regulatory network, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. It can also influence other steps in mRNA maturation and cellular activities, including chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR, and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and dual-track mechanism involving both processive phosphorylation (where the kinase remains attached to the substrate after each phosphorylation round) and distributive phosphorylation steps (where the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 initially binds to a docking groove in the large lobe of the kinase domain of SRPK1. This induces structural changes in SRPK1 and/or the RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. This process continues for several phosphorylation steps in a processive manner (steps 1-8) until the last few steps (approximately steps 9-12). During this time, a mechanical stress unfolds the beta-4 motif in RRM2, which then docks at the SRPK1 docking groove. This also signals RRM2 to begin dissociating, facilitating SRSF1 dissociation after phosphorylation completion. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It negatively regulates HBV replication by reducing pregenomic RNA (pgRNA) packaging efficiency without affecting viral core particle formation. Isoforms 1 and 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in K-562 leukemia cell fate, with isoform 2 promoting proliferation and isoform 1 promoting differentiation. Isoform 2 is found in a multisubunit complex containing seven proteins, named toposome, which separates entangled circular chromatin DNA during chromosome segregation. Isoform 2 interacts with DNAJC8 and AHSA1/AHA1, mediating complex formation with the Hsp70/Hsp90 machinery. Isoform 1 is found in a complex with DHX9, MOV10, MATR3, HNRNPU, NCL, DDX21, HSD17B4, PABPC1, HNRNPM, IGF2BP1, SYNCRIP, RPL3, VIM, YBX1, NPM1, HNRNPA2B1, HNRNPC, RPLP0, RPL7A, and RALY. Isoform 2 binds to IGF2BP1, SYNCRIP, HNRNPA2B1, and HNRNPC. Isoforms 1 and 2 interact with SAFB, which inhibits its activity. Isoform 2 interacts with SAFB2, which inhibits its activity. Isoform 2 interacts with HHV-1 ICP27 protein.
SRPK1 is also known as SFRSK1.
