CELL2007 Molecular Exploration Project
Group 7
Dual Specificity Testis-Specific
Protein Kinase 1
Testis-specific protein kinase 1 (TESK 1) is a 65.1 kDa dual specificity protein kinase capable of phosphorylating serine/threonine and tyrosine [5]. It plays a critical role in actin cytoskeleton organization through the phosphorylation of ser-3 on Cofilin [7, 9]. TESK1 is ubiquitously expressed, however, its expression is higher in the testicular tissue. Thus, TESK1 may play a role in spermatogenesis and other developmental processes [2, 4].
In humans, 3 isoforms exists: 1, 2, and 3. This report mainly focuses on isoform 2 [1]. Structurally, TESK1 consists of a C-terminal proline-rich domain and an N-terminal protein kinase domain. Phylogenetic analysis of TESK1 revealed that it is closely related to LIMK1/2 with 50% sequence homology. Nonetheless, its structure is completely different from LIMK’s. Another TESK family member, TESK2, possesses a similar structure to TESK1. In addition to this, they also display a 48% amino acid sequence similarity. Furthermore, it has been shown that there is high conservation, 80%, in the TESK1 kinase domain in comparison to other members of the kinase superfamily [7, 8].
The TESK1 kinase domain can be further divided into 12 subdomains. Within the highly conserved VIB subdomain is an uncommon sequence motif, DLTSKN, which does not correspond to the consensus sequence for serine/threonine kinases. Unsurprisingly, the same case happens in LIMKs, although they have a slightly different sequence [7, 8, 9]. Various eukaryotes contain a homolog of human TESK 1, ranging from zebra fish to chimpanzees. Moreover, 112 organisms possessed orthologous proteins of TESK1. This data illustrates the conservation of TESK1. To be more specific, human TESK1 has over 90% sequence similarity with its equivalent in rats [6].
Figure 1: A diagram to illustrate the role of TESK in the MT stability pathway. Adapted from http://www.cellsignal.com/contents/science-pathway-research-cytoskeletal/regulation-of-microtubule-dynamics-signaling-pathway/pathways-micro
As mentioned previously, TESK1 is crucial for actin cytoskeletal reorganization through the phosphorylation of cofilin. Actin cytoskeletal organization controls crucial cellular activities, which when unregulated can lead to tumour growth and other disastrous effects. The functions of actin are: motility, adhesion, secretion, cytokinesis, and morphological change. The importance of these processes signifies the need for its careful regulation [5, 10].
The mechanism of TESK1 regulation of the aforementioned processes is as follows (Figure 1) : in its phosphorylated form, the actin severing and depolymerisation activities of cofilin are abolished, which inhibits actin disassembly [9]. When highly expressed, TESK1 induces stress fibre formation and focal adhesion to promote cell migration [4, 11]. Likewise, TESK1 can also inhibit Tao Kinase (TAOK). TAOK facilitates signalling between microtubules and actin. As a consequence, its inhibition affects microtubule dynamics. TESK1 also controls the balance between stable and unstable microtubules [3]. Interestingly, Tao1 binds to Spread1, and in turn TESK1 activity is inhibited by Spread 1- preventing overexpression and cellular overspreading. TESK1 can also bind to actopaxin and 14-3-3, whose association decrease its kinase activity and thus increases actin dynamics. These interactions with TESK1 allow the regulation of actin and microtubules, ensuring the correct amount of activity. However, many facets of TESK1's mechanisms and pathways remain unclear [2, 12].
On our website, we have investigated and analysed TESK1's structure, sequence, interactions and possible modes of action.