Identification of key cytosolic kinases containing evolutionarily conserved kinase tyrosine-based inhibitory motifs (KTIMs).

We previously reported that SHP-1 regulates IRAK-1 activity by binding to an ITIM-like motif found within its kinase domain, which we named kinase tyrosine-based inhibitory motif (KTIM). Herein, we further investigated the presence, number, location, and evolutionary time of emergence of potential KTIMs in many cytosolic kinases, all known to play important roles in the signalling and function of immune cells. We unveil that several kinases contain potential KTIMs, mostly located within their kinase domain and appearing predominantly at the level of early vertebrates becoming highly conserved thereafter. Regarding the KTIMs that were found conserved in both vertebrates and invertebrates, we provide experimental data suggesting that such motifs may have constituted readily available sites that performed new regulatory functions as soon as their binding partners (e.g. SHP-1) appeared in vertebrates. We thus propose KTIMs as novel regulatory motifs in kinases that function through binding to SH2 domain-containing proteins such as SHP-1.