Alternative titles; symbols
HGNC Approved Gene Symbol: STK17B
Cytogenetic location: 2q32.3 Genomic coordinates (GRCh38) : 2:196,133,583-196,176,483 (from NCBI)
Apoptosis, or programmed cell death, is a highly regulated process that is crucial in development. Deregulation of apoptosis is responsible for a wide range of diseases, including autoimmune and neurodegenerative disorders. By sequence homology searches using the catalytic domains of 2 serine/threonine kinases important in the regulation of apoptosis, DAP kinase (600954) and ZIP kinase (603289), Sanjo et al. (1998) identified 2 novel members of the ser/thr protein kinase family, STK17A (604726) and STK17B, which they termed DRAK1 (604726) and DRAK2, respectively. The full-length STK17B cDNA clone encodes a deduced 372-amino acid protein with a molecular mass of 42.34 kD. The putative kinase domain is located at the N terminus and contains all 11 subdomains conserved among ser/thr kinases. STK17A and STK17B share 59.7% amino acid identity. Northern blot analysis revealed that STK17B was expressed in various tissues, such as heart, placenta, liver, and pancreas, as different-sized transcripts, presumably due to differences in the 3-prime untranslated region. Transient transfection of COS-7 cells showed that STK17B localized in nuclei.
Using an in vitro assay, Sanjo et al. (1998) demonstrated that STK17B was capable of autophosphorylation and of phosphorylating myosin light chain as an exogenous substrate, but with lower kinase activity than STK17A. Unlike STK17A, an STK17B mutant lacking the noncatalytic C terminus had higher kinase activity than full-length STK17B. By transiently transfecting COS-7 cells, Sanjo et al. (1998) showed that STK17B localized nuclei even when kinase activity was impaired. NIH 3T3 cells transfected with STK17B expression plasmid displayed morphologic changes typical of cells undergoing apoptosis, but not when transfected with STK17B with an inactivated kinase domain or a truncated noncatalytic C-terminal region. A colony formation assay showed that the apoptosis-inducing activity of STK17B required the intact structure of the entire gene and that STK17A and STK17B shared similar levels of apoptosis-inducing activity.
Gross (2012) mapped the STK17B gene to chromosome 2q32.3 based on an alignment of the STK17B sequence (GenBank AB011421) with the genomic sequence (GRCh37).
Ramos et al. (2008) noted that Drak2 -/- mice exhibit enhanced T-cell activation but are resistant to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (see 126200). They showed that Drak2 -/- T cells required greater tonic signaling during clonal expansion. Apoptosis after stimulation of Drak2 -/- T cells could be prevented by Cd28 (186760) ligation, homeostatic cytokines, or enforced Bclxl (600039) expression. T cell-specific Bclxl expression restored susceptibility of Drak2 -/- mice to EAE and enhanced thymic-positive selection. Ramos et al. (2008) concluded that DRAK2 is selectively important for T-cell survival and that DRAK2 blockade has therapeutic potential for autoimmune disease.
McGargill et al. (2008) showed that, in addition to resistance to EAE, Drak2 -/- mice were resistant to type I diabetes (see 222100) when bred to nonobese diabetic mice. However, Drak2 -/- mice were susceptible to other models of autoimmunity and were normally resistant to acute viral infection. Adoptive transfer experiments indicated that resistance to disease was intrinsic to T cells and was due to loss of T-cell survival under conditions of chronic autoimmune stimulation. McGargill et al. (2008) concluded that T-cell survival depends on a balance of T-cell receptor and costimulatory signals and that DRAK2 deficiency can affect autoimmune disease susceptibility without generalized suppression of the immune system.
Gross, M. B. Personal Communication. Baltimore, Md. 5/3/2012.
McGargill, M. A., Choy, C., Wen, B. G., Hedrick, S. M. Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease. J. Immun. 181: 7593-7605, 2008. [PubMed: 19017948] [Full Text: https://doi.org/10.4049/jimmunol.181.11.7593]
Ramos, S. J., Hernandez, J. B., Gatzka, M., Walsh, C. M. Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity. J. Immun. 181: 7606-7616, 2008. [PubMed: 19017949] [Full Text: https://doi.org/10.4049/jimmunol.181.11.7606]
Sanjo, H., Kawai, T., Akira, S. DRAKs, novel serine/threonine kinases related to death-associated protein kinase that trigger apoptosis. J. Biol. Chem. 273: 29066-29071, 1998. [PubMed: 9786912] [Full Text: https://doi.org/10.1074/jbc.273.44.29066]