ICK is conserved and almost all metazoans and some unicellular species have homologs of both MAK and ICK. Human ICK MRK and human MAK are nearly identical in the kinase domain. Danio rerio has one gene that encodes a protein more similar to ICK than MAK. This genome is an anomaly, as other teleost fishes have both ICK and MAK genes. ICK message is highly e pressed in developing retina in zebra fish. Interestingly, ICK or MAK e pression is greatly increased in retinal cancer compared to normal retina according to data at the Cancer Genome Anatomy Project. Our prior work established ICK as the prototype for a group of CDK and MAPK like protein kinases regulated by phosphorylation in a TDY motif. No canonical MAP kinase cascades have yet emerged for activation of ICK, in its limited study.

An alternative mechanism is transcriptional regulation followed by activation by active protein kinases. The ICK homolog in S. cerevisiae is regu lated by transcription, and is subsequently phosphory lated in the T Y motifs dependent upon yeast CAK. In an insightful commentary, Adachi and Lieber noted that of twenty, functional bidirectional promoters reported in the literature at the time, several directed transcription of genes implicated in DNA repair includ ing BRCA1 NBR2, DNA PKcs MCM4, ATM NPAT, DHFR MSH3, and Ku86 TERP. While not unique to this class, they concluded placement of genes into bidirec tional promoters is a common scenario for DNA repair genes. Clearly, this correlation does not imply anything about function of FB 9 or ICK.

Nevertheless, this is of interest since ICK has interactors that may have some role in DNA repair. FB 9 is predicted to encode an F bo protein. F bo proteins contain a conserved domain that interacts directly with Skp1 as one of the components of a SCF ubiquitin ligase. The F bo protein provides a specific interaction that specifically recruits a substrate, possibly in a specific form for degradation by linkage to ubiq uitin. The substrate specificity of FB 9 is unknown. FB 9 could produce three forms based on predicted transcripts. FB 9 has a possible homolog in S. cerevisiae named Hrt3p, discovered in a single Carfilzomib genome search of S. cerevisiae using SSEARCH. Reciprocally, a search of NCBI human refer ence proteins with Hrt3p using SSEARCH finds FB 9 as the very first hit. Hrt3p is a putative nuclear ubiquitin ligase component based on large scale studies.

Hrt3p interacts with Cdc53p and Skp1p by affinity capture mass spectrometry, and shows dos age lethality with cdc34. The intestinal epithelium has advantages for studies of differentiation, one being the segregation of the epithe lium into defined zones containing stem cells, zones for proliferating transit cells, and a zone of non proliferating differentiated enterocytes.