Identification of Key Cytosolic Kinases Containing Evolutionarily Conserved Kinase Tyrosine-based Inhibitory Motifs (KTIMs).
Posted by: Issa Abu-Dayyeh
I have posted an earlier article to talk about our PLoS NTD paper where we have described a novel strategy by which Leishmania was able to inhibit TLR-mediated macrophage activation through its ability to inhibit IRAK-1 kinase activity by activating the protein tyrosine phosphatase (PTP) SHP-1.
We have identified the site of binding between SHP-1 and IRAK-1 to be an evolutionarily conserved ITIM-like motif, which we called a kinase tyrosine-based inhibitory motif (KTIM). In this newly-published paper in Developmental and Comparative Immunology, Abu-Dayyeh et al. present evolutinary as well as experimental data that propose that KTIMs could potentially represent a novel regulatory site involved in the control of the kinase activity of many key kinases involved in siganlling pathways of immune cells. Although this work awaits to be further explored by other researches, I believe this work could open various doors towards many important discoveries in the field of immunology.
Here is the abstract of the paper:
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. Copyright © 2009. Published by Elsevier Ltd.
Posted by Issa Abu-Dayyeh
I will hereby post the author summary of my most recent publication regarding modulation of macrophage signaling by the Leishmania parasite. The paper has been published on the 23rd of December 2008 in the Public Library of Science (PLoS) Neglected Tropical Diseases, and demonstrates for the first time the ability of Leishmania to inactivate IRAK-1 through its ability to activate host PTP-SHP-1.
Citation: Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, et al. (2008) Leishmania-Induced IRAK-1 Inactivation Is Mediated by SHP-1 Interacting with an Evolutionarily Conserved KTIM Motif. PLoS Negl Trop Dis 2(12): e305. doi:10.1371/journal.pntd.0000305
Here is the author summary of the paper:
Leishmania developed several methods to seize control of macrophage signalling pathways in an effort to inactivate their killing abilities. One effective method utilized by the parasite is the activation of host protein tyrosine phosphatases, specifically SHP-1. This increased phosphatase activity contributes to the inactivation of signalling molecules involved in critical macrophage functions such as NO and cytokine production. Interestingly, the absence of SHP-1 results in stronger macrophage inflammatory responses to a bacterial cell wall component known as LPS, a molecule detected by macrophages through Toll-like receptors (TLRs). This observation suggested a role for SHP-1 in the regulation of TLR signalling. Our study reveals that upon Leishmania infection, SHP-1 is able to rapidly bind to and inactivate a critical kinase (IRAK-1) in this pathway. This regulatory binding was shown to be mediated by an evolutionarily conserved motif identified in the kinase. This motif was also present in other kinases involved in Toll signalling and therefore could represent a regulatory mechanism of relevance to many kinases. This work not only reports a unique mechanism by which Leishmania can avoid harmful TLR signalling, but also provides a platform on which extensive investigation on host evasion mechanisms and regulation of cellular kinases can be gained.
For further information please check the citation below to read the whole paper. PLoS is an open-access journal and therefore offers free access to its contents to anybody anywhere in the world!
P.S.: Abstract translations are also available in the following languages: Arabic, French, Spanish, and Farsi.