Kinase Family ULK

Kinase Classification: Group Other: Family ULK

ULK (Unc-51-Like Kinases) cytoplasmic kinases are found in all eukaryotes, involved in autophagy, hedgehog signaling and cytokinesis.

The ULK family has the following subfamilies:

Classification, Functions and Evolution

ULK kinases are found in all eukaryotes examined. There are four main subfamilies: Fused, ULK1 and ULK4 are primordial and ULK3 is found in holozoans.

Fused kinases are best known in Drosophila for involvement in hedgehog signaling. However, a mouse knockout shows no obvious hedgehog-pathway phenotype [1], though it does suffer from hydrocephalus, possibly indicating a cilium function.

ULK1 kinases are involved in autophagy (yeast Atg1 and human ULK1 and ULK2).

ULK3 is also implicated in hedgehog signaling [2] and in autophagy-mediated senescence [3]. Several GWAS studies show linkage to blood pressure and caffeine consumption. The ULK3 kinase domain may be more similar to protist ULK1 than is holozoan ULK1, but ULK3 lacks the DUF3543 domain of ULK1, suggesting that holozoan ULK1 and ULK3 may have sub-functionalized the functions of pre-holozoan ULK1.

ULK4 is a pseudokinase in all species. Human ULK4 has been genetically linked to multiple myeloma by GWAS, and may be linked to hydrocephalus and blood pressure (similar to Fused and ULK3, respectively). The Arabidopsis homolog, RUK, is involved in cytokinesis [4].

Domain Structure

All ULK kinases have an N-terminal kinase domain and most have C-terminal extensions. ULK1 has a C-terminal DUF3543 domain, though plant homologs are too remote to be picked up by the current Pfam model. Fused proteins have HEAT repeats, and ULK3 often have MIT domains. Some ULK4 have weak ARM repeats.

References

2. Maloverjan A, Piirsoo M, Michelson P, Kogerman P, and Osterlund T. Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway. Exp Cell Res. 2010 Feb 15;316(4):627-37. DOI:10.1016/j.yexcr.2009.10.018 |
3. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavaré S, Arakawa S, Shimizu S, Watt FM, and Narita M. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009 Apr 1;23(7):798-803. DOI:10.1101/gad.519709 |
4. Krupnova T, Sasabe M, Ghebreghiorghis L, Gruber CW, Hamada T, Dehmel V, Strompen G, Stierhof YD, Lukowitz W, Kemmerling B, Machida Y, Hashimoto T, Mayer U, and Jürgens G. Microtubule-associated kinase-like protein RUNKEL needed [corrected] for cell plate expansion in Arabidopsis cytokinesis. Curr Biol. 2009 Mar 24;19(6):518-23. DOI:10.1016/j.cub.2009.02.021 |
5. Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, Carano RA, van Hoy M, Ramirez J, Ogasawara AK, McFarland LM, Filvaroff EH, French DM, and de Sauvage FJ. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol. 2005 Aug;25(16):7054-68. DOI:10.1128/MCB.25.16.7054-7068.2005 |