INTEGRIN REGULATION · Functional analysis of the kinome and phosphatome as determinants of integrin phosphorylation in cancer

Functional analysis of the kinome and phosphatome as determinants of integrin phosphorylation in cancer

Cancer dissemination from a primary tumour is a complex process that is mediated by cell-cell and cell-ECM (extracellular matrix) interactions. Integrin adhesion receptors are key signalling molecules that mediate the extracellular binding of ECM by cells, and the respective intracellular signalling resultant from that interaction. As such, they have been implicated in every step of cancer progression, as well as in diseases such as fibrosis and autoimmunity. While the importance of these receptors has been known for some time, targeting their extracellular domains has been largely unsuccessful in the clinic. Hence, new avenues for the therapeutic modulation of integrin activity are required in order to target their role in several diseases, especially in cancer therapies that are ham-strung by resistance to chemotherapeutics, anoikis and metastatic dissemination. Given that the cytoplasmic domains of integrin adhesion receptors are essential hubs for protein-protein interactions, and that these domains are responsible for the cellular response to the extracellular environment, there remains a surprising lack in known regulators for integrin phosphorylation. Phosphorylation on specific residues is a reversible and highly dynamic process that can modulate the activity and protein-protein complex formation of many proteins within the cell. This process is bidirectionally regulated by kinases and phosphatases, which are themselves often druggable targets for targeted cancer therapies. As a proof-of-concept adhesion receptor, the fellow chose integrin beta1, as it is central to adhesion to the largest number of ECM ligands and there is experimental evidence for phosphorylation of this receptor on two tyrosine residues at the NPxY(783/795) sites within the cytoplasmic domain. Thus INTEGRIN REGULATION had three specific research objectives (SOs) that were focused on understanding the regulation and role of phosphorylation in the intracellular domains of integrin beta1. SO1: Identification of novel regulatory kinases and/or phosphatases by unbiased screening approaches. SO2: Confirmation of interactions using super-resolution imaging. SO3: Functional assessment of identified kinases and/or phosphatases.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз