Kinase Family STK33

Kinase Classification: Group CAMK: Family STK33

STK33 is a CAMK-like kinase implicated in cancer growth pathways.

Evolution

STK33 is found in animals and some fungi (chytrids) but is lost in both Drosophila and C. elegans and related species (all nematodes, and almost all Dipteran insects).

Domain Structure

STK33 is about 500 AA long, with a kinase domain in the middle, and unannotated sequences on either side that are poorly conserved in vertebrates and absent from many invertebrate gene predictions. A short region of ~15 AA is conserved at the N-terminal edge of the kinase and ~11 AA on the C-terminal edge. Alphafold shows no structure outside of the kinase domain other than a short predicted helix, and InterProscan predicts disorder in most of the terminal regions.

Expression

Human STK33 is most highly expressed in testis, but is found in all tissues, particularly in ciliated cells (Proteinatlas). It is found in the cytoplasm, nucleoplasm and nucleoli.

Functions

STK33 has been implicated in development of many cancers. STK33 overexpression drove proliferation, migration and EMT and knockdown inhibited growth and activated apoptosis in cell lines from several cancers, including pancreatic [1], small cell lung cancer [2], gastric [3], hepatocellular carcinoma (HCC) [4], large cell lung cancer [5], as well as in mouse models of HCC.

Molecularly, STK33 is known to autophosphorylate [6], to bind and phosphorylated ERK2 [7], and to bind to and activate c-myc in liver cells [4], both of which may be pro-oncogenic. It also binds to and phosphorylates the N-terminal portion of vimentin [6].

STK33 is induced by HIF1a in pancreatic cancer [1], and it binds and is stabilized by the HSP90/CDC37 chaperone complex [8]. An initial report indicating a synthetic lethal role in Kras-driven cancers [9] has since been refuted [10]. In SCLC cells, it activated S6K1/BAD signaling [2]. In NSCLC cell lines and tissue, the micro-RNA miR-107 suppresses growth and downregulates STK33[11].

The STK33 locus has also been implicated by GWAS with obesity [12], and in tyrosine metabolism: STK33 phosphorylates HPD (4-hydroxyphenylpyruvic acid dioxygenase) on T382, recruiting the FHA domain-containing PELI1, which induces ubiquitin-mediated degradation of HPD [13].

References

1. Kong F, Kong X, Du Y, Chen Y, Deng X, Zhu J, Du J, Li L, Jia Z, Xie D, Li Z, and Xie K. STK33 Promotes Growth and Progression of Pancreatic Cancer as a Critical Downstream Mediator of HIF1α. Cancer Res. 2017 Dec 15;77(24):6851-6862. DOI:10.1158/0008-5472.CAN-17-0067 |
2. Sun EL, Liu CX, Ma ZX, Mou XY, Mu XA, Ni YH, Li XL, Zhang D, and Ju YR. Knockdown of human serine/threonine kinase 33 suppresses human small cell lung carcinoma by blocking RPS6/BAD signaling transduction. Neoplasma. 2017;64(6):869-879. DOI:10.4149/neo_2017_608 |
3. Kong F, Sun T, Kong X, Xie D, Li Z, and Xie K. Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition. Clin Cancer Res. 2018 May 15;24(10):2440-2451. DOI:10.1158/1078-0432.CCR-17-3346 |
4. Yang T, Song B, Zhang J, Yang GS, Zhang H, Yu WF, Wu MC, Lu JH, and Shen F. STK33 promotes hepatocellular carcinoma through binding to c-Myc. Gut. 2016 Jan;65(1):124-33. DOI:10.1136/gutjnl-2014-307545 |
5. Wang P, Cheng H, Wu J, Yan A, and Zhang L. STK33 plays an important positive role in the development of human large cell lung cancers with variable metastatic potential. Acta Biochim Biophys Sin (Shanghai). 2015 Mar;47(3):214-23. DOI:10.1093/abbs/gmu136 |
6. Brauksiepe B, Mujica AO, Herrmann H, and Schmidt ER. The Serine/threonine kinase Stk33 exhibits autophosphorylation and phosphorylates the intermediate filament protein Vimentin. BMC Biochem. 2008 Sep 23;9:25. DOI:10.1186/1471-2091-9-25 |
7. Zhang S, Wu H, Wang K, and Liu M. STK33/ERK2 signal pathway contribute the tumorigenesis of colorectal cancer HCT15 cells. Biosci Rep. 2019 Mar 29;39(3). DOI:10.1042/BSR20182351 |
8. Azoitei N, Hoffmann CM, Ellegast JM, Ball CR, Obermayer K, Gößele U, Koch B, Faber K, Genze F, Schrader M, Kestler HA, Döhner H, Chiosis G, Glimm H, Fröhling S, and Scholl C. Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33. J Exp Med. 2012 Apr 9;209(4):697-711. DOI:10.1084/jem.20111910 |
9. Scholl C, Fröhling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY, Silver SJ, Tamayo P, Wadlow RC, Ramaswamy S, Döhner K, Bullinger L, Sandy P, Boehm JS, Root DE, Jacks T, Hahn WC, and Gilliland DG. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009 May 29;137(5):821-34. DOI:10.1016/j.cell.2009.03.017 |
10. Babij C, Zhang Y, Kurzeja RJ, Munzli A, Shehabeldin A, Fernando M, Quon K, Kassner PD, Ruefli-Brasse AA, Watson VJ, Fajardo F, Jackson A, Zondlo J, Sun Y, Ellison AR, Plewa CA, San MT, Robinson J, McCarter J, Schwandner R, Judd T, Carnahan J, and Dussault I. STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res. 2011 Sep 1;71(17):5818-26. DOI:10.1158/0008-5472.CAN-11-0778 |
11. Wei X, Lei Y, Li M, Zhao G, Zhou Y, Ye L, and Huang Y. miR-107 inhibited malignant biological behavior of non-small cell lung cancer cells by regulating the STK33/ERK signaling pathway in vivo and vitro. J Thorac Dis. 2020 Apr;12(4):1540-1551. DOI:10.21037/jtd.2020.03.103 |
12. Rask-Andersen M, Moschonis G, Chrousos GP, Marcus C, Dedoussis GV, Fredriksson R, and Schiöth HB. The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children. PLoS One. 2013;8(8):e71353. DOI:10.1371/journal.pone.0071353 |
13. Xie Y, Lv X, Ni D, Liu J, Hu Y, Liu Y, Liu Y, Liu R, Zhao H, Lu Z, and Zhou Q. HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage. Nat Commun. 2019 Sep 19;10(1):4266. DOI:10.1038/s41467-019-12011-0 |