The Role of novel PKC Kinases in Integrin Activation

Integrins represent a family of cell adhesion receptors mediating cell interaction with the extracellular matrix ligands. Their ligand-binding activity is tightly regulated and, when defective, gives rise to thrombosis or inflammation and contributes to cancer progression. To date, the key steps of integrin activation in response to both extracellular and intracellular signals are well described, however, the counteracting processes resulting in receptor inactivation remain incompletely understood. The host laboratory has pioneered research in this area by screening to identify integrin inactivating proteins involved in neuronal disorders, cell migration and cancer. Although the novel subfamily of protein kinase C (nPKC) has emerged from these screens as putative integrin inhibitors, the role of these kinases in regulation of integrin-mediated signalling remains to be investigated. Benefiting from my strong methodological proficiency in protein kinase research and the host laboratory's extensive expertise in integrin biology in cancer, I aim to address the role of nPKCs in regulation of integrin activation from both mechanistic and pre-clinical points of view. I expect to identify new cancer relevant signalling nodes by executing mechanistic in vitro studies with specifically engineered kinase mutants, state-of-the art cancer cell biology and imaging, followed by in vivo pre-clinical cancer studies in cancer models and patient sample cohorts. The result of this innovative and interdisciplinary project will represent a valuable basis for potential design of drug targeting strategy and therapeutic intervention not only for treatment of cancer, but also of other diseases where nPKCs and integrins are implicated.