Human-Mouse Kinome Update

This page presents our unpublished work on the completion and comparison of the mouse and human kinomes. It updates our human kinome paper [1] and our mouse kinome paper [2] with several novel kinases, many sequence corrections and new isoforms (even relative to the current public databases), and analysis of why some claimed kinases may not be correct.

New mouse and human protein kinases

Four-Jointed (FJ)

FJ is a PKL-fold kinase family, weakly related to PI4' kinases. A Drosophila homolog has been shown to phosphorylate proteins within the Golgi apparatus. Both human and mouse have four clear members of the family and two more possible remote homologs.

New candidate atypical kinases

Several more proteins that have no sequence similarity to known kinases have since been reported to have catalytic activity. As with other atypical kinases, it is difficult to conclusively prove lack of contamination. These include BAZ, COL4A3BP, BLVRA, GTF2F1 and CPNE. See the Atypical Kinase page for more details.

Sequence Updates

Detailed curation of genomic and expressed sequences allowed us to update the longest forms of 36 human kinases and 138 mouse kinases. Many include new alternative splice forms, but about two dozen represent corrections relative to the original kinome and to current public sequence databases. Updated sequences and domain annotations are available through KinBase.

Differences between human and mouse kinomes

95% of all human protein kinases have mouse orthologs. The differences in kinase count between the two genomes are mostly in recently-evolved and poorly-annotated genes, suggesting that most do not have particularly important functions.

Retrotransposed gene copies

Three human-specific genes are intronless (retrotrasponsed) close copies of intron-containing kinases. These are TAF1L (duplicate of TAF1, expressed specifically in testis), CK1a2 (CK1a1 copy), and PKACg (PKACa copy). All appear to be expressed, functional genes, under evolutionary constraint.

Both species have additional retrotransposed copies which are too recent to use Ka/Ks analysis to determine if they are under selective pressure. They have been given the "-rs" (-related sequence) tag. They are STLK6-rs and CK2a2-rs in human, and CK2a2-rs and NDR2-rs in mouse. The CK2a2-rs genes are not orthologous: each is more similar to its in-species paralog than to the other -rs and they occupy different genomic loci.

Pseudogenized genes

KSGC, CYGX, TSSK5 and PLK5 are functional genes in mouse, and found in human as pseudogenes. Similarly, CDK3 is a human gene with an orthologous mouse pseudogene. All of these genes are found in only a subset of vertebrates, with vertebrate paralogs, and so may lack highly-unique functions.

Others

PSKH2, DRAK1 and GPRK7 are found in human and thought to be lost from mouse, due to their presence in other mammals. GPRK7 is a likely cone opsin kinase [3], and its loss in mouse may relate to changes in color vision. DRAK1 is an apoptosis-associated kinase, mapping close to a syntenic breakpoint between mouse and human, which may be the cause of its loss in mouse [4].

The large expansion of MARK kinases (23 members not found in human) in mouse has a largely independent similar expansion in rat. Human has 25 MARK pseudogenes, but none are obvious orthologs of the mouse genes, suggesting that this is a family with high turnover in mammals.

Human-specific Kinases

PRKY is a likely primate-specific duplication of the X-chromosome PRKX gene, found on the Y chromosome. The human gene is likely a pseudogene (details).

At least one other human pseudogene has been inferred to have function: Brafps is a Braf pseudogene with an inferred role in Braf-WT thyroid cancers, through cryptic activation of MAPK signaling [5] possibly through upregulation Braf [6]. Despite the citation, the mouse Braf pseudogene is not orthologous to the human one.

TAF1L is a retrotransposed copy of TAF1 which is expressed in the testis and under evolutionary constraint, as measured by Ka/Ks. It is also found in chimp.

CDK3 is a pseudogene in mouse, though full-length in the related Mus spretus. It is also a pseudogene in rat. It appears to be a mammalian-specific copy of CDK2.

Mouse-specific Kinases

PLK5 is an active gene in mouse, but a pseudogene in human (details).

TSSK5 is also detected as a pseudogene in human. The TSSK family is among the most dynamic in vertebrate evolution, with multiple duplications and deletions seen. This may be related to it's expression in the testis and possible function in reproduction.

References

1. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912-34. DOI:10.1126/science.1075762 |
2. Caenepeel S, Charydczak G, Sudarsanam S, Hunter T, and Manning G. The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11707-12. DOI:10.1073/pnas.0306880101 |
3. Chen CK, Zhang K, Church-Kopish J, Huang W, Zhang H, Chen YJ, Frederick JM, and Baehr W. Characterization of human GRK7 as a potential cone opsin kinase. Mol Vis. 2001 Dec 21;7:305-13.
4. Fitzgerald J and Bateman JF. Why mice have lost genes for COL21A1, STK17A, GPR145 and AHRI: evidence for gene deletion at evolutionary breakpoints in the rodent lineage. Trends Genet. 2004 Sep;20(9):408-12. DOI:10.1016/j.tig.2004.07.002 |
5. Zou M, Baitei EY, Alzahrani AS, Al-Mohanna F, Farid NR, Meyer B, and Shi Y. Oncogenic activation of MAP kinase by BRAF pseudogene in thyroid tumors. Neoplasia. 2009 Jan;11(1):57-65. DOI:10.1593/neo.81044 |
6. Karreth FA, Reschke M, Ruocco A, Ng C, Chapuy B, Léopold V, Sjoberg M, Keane TM, Verma A, Ala U, Tay Y, Wu D, Seitzer N, Velasco-Herrera Mdel C, Bothmer A, Fung J, Langellotto F, Rodig SJ, Elemento O, Shipp MA, Adams DJ, Chiarle R, and Pandolfi PP. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell. 2015 Apr 9;161(2):319-32. DOI:10.1016/j.cell.2015.02.043 |