Kinase Subfamily CRIK
Kinase Classification: Group AGC: Family DMPK: Subfamily CRIK
CRIK (Citron Rho-Interacting Kinase) is a metazoan kinase with a conserved function in cytokinesis.
Evolution
CRIK is found as a single gene in most animals, including sponges, but is absent from C. elegans.
Domain Structure
CRIK proteins are about 2000 AA long, with an N-terminal kinase, a middle coiled-coiled section including a rho binding domain and several TMF domains, and a C-terminal C1-PH-CNH domain cluster, similar to other DMPK kinases. Mammalian CRIK, known as citron kinase, has an alternative transcriptional start site that encodes a protein, called CIT-N, or Citron, that lacks the kinase domain, and which is mostly expressed in post-mitotic neurons.
Functions
CRIK is involved in cytokinesis in both mammals and Drosophila, and is implicated in both cancer and neuronal development in mammals. Human CRIK (Citron Kinase) phosphorylates the myosin light chain, MYL9/MRLC1 on T19/S20 [1] (S20 is also phosphorylated by the related MRCKa and ROCK1 kinases). However, much of its role in cytokinesis may be by acting as a scaffold protein for other cytokinesis components [2]. Drosophila CRIK (sticky) interacts with the kinesins Nebbish and Pavarotti, and human CRIK interacts with their orthologs, KIF14 and KIF23/MKLP1 [3] to promote midbody formation during cytokinesis. In Drosophila, CRIK/Sticky catalytic activity was required for this function.
In human and Droospihla, CRIK is required for abscission (breakage of the intracellular bridge between two daughter cells) and midbody formation. CRIK interacts with RhoA in this function [4]
Human Citron is mostly highly expressed in brain, and mutations that alter splicing or kinase activity lead to microcephaly [5, 6], as do knockouts in mouse and rat, and mutations in its interacting partner, the kinesin KIF14 [7]
Human CRIK is also reported to be activated by CCL21, and to phosphorylate the transcription factor GLI2 in breast cancer cells, in a pathway involving RhoC interaction [8]
References
- Yamashiro S, Totsukawa G, Yamakita Y, Sasaki Y, Madaule P, Ishizaki T, Narumiya S, and Matsumura F. Citron kinase, a Rho-dependent kinase, induces di-phosphorylation of regulatory light chain of myosin II. Mol Biol Cell. 2003 May;14(5):1745-56. DOI:10.1091/mbc.e02-07-0427 |
- D'Avino PP. Citron kinase - renaissance of a neglected mitotic kinase. J Cell Sci. 2017 May 15;130(10):1701-1708. DOI:10.1242/jcs.200253 |
- Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, and D'Avino PP. Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9782-7. DOI:10.1073/pnas.1301328110 |
- pmid= 21849473
- Shaheen R, Hashem A, Abdel-Salam GM, Al-Fadhli F, Ewida N, and Alkuraya FS. Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans. Hum Genet. 2016 Oct;135(10):1191-7. DOI:10.1007/s00439-016-1722-2 |
- Li H, Bielas SL, Zaki MS, Ismail S, Farfara D, Um K, Rosti RO, Scott EC, Tu S, Chi NC, Gabriel S, Erson-Omay EZ, Ercan-Sencicek AG, Yasuno K, Çağlayan AO, Kaymakçalan H, Ekici B, Bilguvar K, Gunel M, and Gleeson JG. Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet. 2016 Aug 4;99(2):501-10. DOI:10.1016/j.ajhg.2016.07.004 |
- Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Höhne W, Noegel AA, Al-Owain M, Hörtnagel K, Stöbe P, Baig SM, Nürnberg P, Alkuraya FS, Hahn A, and Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577. DOI:10.1002/ana.25044 |
- Xing Z, Lin A, Li C, Liang K, Wang S, Liu Y, Park PK, Qin L, Wei Y, Hawke DH, Hung MC, Lin C, and Yang L. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell. 2014 Nov 20;159(5):1110-1125. DOI:10.1016/j.cell.2014.10.013 |
