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HEIndividual fellowship2023–2025

nPKCInAction · The Role of novel PKC Kinases in Integrin Activation

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-04-01 → 2025-03-31
EU contribution
€215,534
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

The Role of novel PKC Kinases in Integrin Activation

Integrins are a family of transmembrane adhesion proteins that connect the extracellular matrix components to the cell cytoskeleton. In this way, integrin adhesions act as receptors translating information from the extracellular environment into intracellular responses. While balanced integrin activity is crucial in maintaining cell survival, cell migration, and correct tissue architecture and renewal, its deregulation is frequently associated with the development of diseases such as fibrosis and cancer. While the mechanisms of integrin activation are well studied, regulation of integrin adhesion dynamics remains less well understood. Although this project was initially aimed at identifying the role of novel family of protein kinase C (nPKC) in regulation of integrin activity, the initial results did not reveal any substantial effect of nPKCs on this process. Consequently, we changed our focus to adhesion protein from Tensin family, Tensin 1 (TNS1), and its role in regulating integrin adhesion dynamics. Specifically, we were interested in the role of TNS1 liquid-liquid phase separation (LLPS) in this process, in other words, its ability to form biomolecular condensates. Biomolecular condensation, a rapidly emerging field over the past decade, has been implicated in intracellular protein compartmentalisation resulting in formation of membraneless organelles, regulation of cell signalling, and translation of mechanical cues into cellular responses. It has been previously reported that several components of integrin adhesions undergo LLPS, directly influencing integrin activation. This prompted us to explore the role of TNS1 LLPS in integrin dynamics with a particular focus on the following objectives: 1) to validate the ability of TNS1 to undergo LLPS in cancer cells both under exogenous expression and at endogenous protein levels; 2) to identify the main components of TNS1 condensates and to establish their role in regulation of integrin adhesion signalling; 3) to elucidate the molecular determinants driving TNS1 LLPS and assess their functional effects on cancer cell behaviour. The results of this project significantly broaden our understanding of cell adhesion biology and open up new avenues for translating these findings into innovative therapeutic approaches.

Data: CORDIS, © European Union

Project objective

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.

Original text from CORDIS.

Participants

  • TURUN YLIOPISTO · TurkuCoordinatorFinland

Links

Data: CORDIS, © European Union