Kinase Family YANK
Kinase Classification: Group AGC: Family YANK
Evolution
YANK is found in fungi and animals, though has been lost from the lineage that includes Saccharomyces cerevisiae. There are three vertebrate members, YANK1-3 (STK32A, STK32B, STK32C)
Domain Structure
YANK kinases have a AGC kinase domain and a divergent AGC tail that likely retains the hydrophobic motif (https://www.biorxiv.org/content/10.1101/2020.03.04.976555v1.full). Most YANK have a starting "MG" motif and human YANK1 and YANK2 are myristoylated on this site [1], and myristoylation relocalizes YANK1 from the cytoplasm to the plasma membrane [2]. A detailed structural analysis of YANK1 (https://www.biorxiv.org/content/10.1101/2020.03.04.976555v1.full) shows that it has an unusual preference for acidic residues in substrates, and a modified mechanism for the hydrophobic motif to wrap around to the kinase active site.
Functions
These kinases are very poorly studied. In human, multiple members have been associated with cell growth and cancer: YANK1/STK32A is a target of the RUNX2 transcription factor and facilitates cell growth and survival and NFkB phosphorylation in cell lines [3], while YANK3 was shown overexpressed and correlated with poor prognosis in bladder cancer [4], and knockdown blocked proliferation and migration in cell lines, and tumor growth in mouse xenografts [4].
Two members have also been associated with mood disorders: YANK2/STK32B has a promoter SNP associated with adolescent anxiety in one study [5], while a methylation site in YANK3/STK32C was associated with adolescent depression [6]. YANK2 has been genetically associated with the disease essential tremor (ET) in several studies, and is overexpressed in cerebellum from ET patients [7]. SNPs in YANK2 and another ET gene, CTNNA3 were also associated with suicidal behavior [8]
The three human genes have selective tissue expression (Entrez Gene, GTEx). YANK3 is most highly expressed in brain, and strong expression of an alternative isoform in testis, YANK2 has elevated expression in kidney and testis, and YANK1 is the most evenly expressed. YANK2 antibody staining was seen in cytoplasm and nucleus [4]
The fly and nematode YANKs have not been functionally explored.
References
- Takamitsu E, Otsuka M, Haebara T, Yano M, Matsuzaki K, Kobuchi H, Moriya K, and Utsumi T. Identification of Human N-Myristoylated Proteins from Human Complementary DNA Resources by Cell-Free and Cellular Metabolic Labeling Analyses. PLoS One. 2015;10(8):e0136360. DOI:10.1371/journal.pone.0136360 |
- Takamitsu E, Fukunaga K, Iio Y, Moriya K, and Utsumi T. Cell-free identification of novel N-myristoylated proteins from complementary DNA resources using bioorthogonal myristic acid analogues. Anal Biochem. 2014 Nov 1;464:83-93. DOI:10.1016/j.ab.2014.07.006 |
- Ma F, Xie Y, Lei Y, Kuang Z, and Liu X. The microRNA-130a-5p/RUNX2/STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer. BMC Cancer. 2020 Jun 22;20(1):580. DOI:10.1186/s12885-020-07056-0 |
- Sun E, Liu K, Zhao K, and Wang L. Serine/threonine kinase 32C is overexpressed in bladder cancer and contributes to tumor progression. Cancer Biol Ther. 2019;20(3):307-320. DOI:10.1080/15384047.2018.1529098 |
- Ciuculete DM, Boström AE, Tuunainen AK, Sohrabi F, Kular L, Jagodic M, Voisin S, Mwinyi J, and Schiöth HB. Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents. J Psychiatr Res. 2018 Jul;102:44-51. DOI:10.1016/j.jpsychires.2018.03.008 |
- Dempster EL, Wong CC, Lester KJ, Burrage J, Gregory AM, Mill J, and Eley TC. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol Psychiatry. 2014 Dec 15;76(12):977-83. DOI:10.1016/j.biopsych.2014.04.013 |
- Liao C, Sarayloo F, Vuokila V, Rochefort D, Akçimen F, Diamond S, Houle G, Laporte AD, Spiegelman D, He Q, Catoire H, Dion PA, and Rouleau GA. Transcriptomic Changes Resulting From STK32B Overexpression Identify Pathways Potentially Relevant to Essential Tremor. Front Genet. 2020;11:813. DOI:10.3389/fgene.2020.00813 |
- Galfalvy H, Haghighi F, Hodgkinson C, Goldman D, Oquendo MA, Burke A, Huang YY, Giegling I, Rujescu D, Bureau A, Turecki G, and Mann JJ. A genome-wide association study of suicidal behavior. Am J Med Genet B Neuropsychiatr Genet. 2015 Oct;168(7):557-63. DOI:10.1002/ajmg.b.32330 |
