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Streptomyces species are native inhabitants of soil, a natural environment where nutrients can be scarce and competition fierce. They have evolved ways to metabolize unusual nutrients, such as purines and its derivatives, which are highly abundant in soil. Catabolism of these uncommon carbon and nitrogen sources needs to be tightly regulated in response to nutrient availability and environmental stimulus. Recently, the allantoin degradation pathway was characterized in Streptomyces coelicolor. However, there are questions that remained unanswered, particularly regarding pathway regulation. Here, using a combination of proteomics and genetic approaches, we identified the negative regulator of the allantoin pathway, AllR. In vitro studies confirmed that AllR binds to the promoter regions of allantoin catabolic genes and determined the AllR DNA binding motif. In addition, effector studies showed that allantoic acid, and glyoxylate, to a lesser extent, inhibit the binding of AllR to the DNA. Inactivation of AllR repressor leads to the constitutive expression of the AllR regulated genes and intriguingly impairs actinorhodin and undecylprodigiosin production. Genetics and proteomics analysis revealed that among all genes from the allantoin pathway that are upregulated in the allR mutant, the hyi gene encoding a hydroxypyruvate isomerase (Hyi) is responsible of the impairment of antibiotic production.

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.

Cancer is a group of diseases that affects almost every organ of the human body. A normal cell transforms into a cancer cell as a consequence of cumulative failures that alter diverse cellular processes such as cell proliferation, adhesion, migration, and cell death. Focal Adhesion Kinase (FAK) is a ubiquitous protein that is involved in all these cellular processes. Therefore, it is not surprising that FAK plays important roles in cancer; in fact, it has been linked to tumour progression or regression depending on the cellular and genetic context. We used Drosophila melanogaster as a model organism to study FAK’s duality in cancer. In this thesis we describe two novel roles of Drosophila FAK (FAK56): as a tumour suppressor within receptor tyrosine kinases (RTKs)-driven contexts, and as a tumour promoter by inhibiting cell death in nervous tissues. We investigated how FAK56 regulates signalling resulting from the overexpression of RTKs RET and EGFR. Our data indicated that FAK is a suppressor of RTKs in fly epithelia. This was also observed in human cancer cell lines, suggesting an evolutionary conserved mechanism. On the other hand, we found FAK56 prevented caspase-dependent cell death and uncovered a novel link between FAK56 and Relish, the Drosophila homologue of human NF-κB: Relish mutants suppressed FAK56 loss-induced cell death in the larval central nervous system and eye imaginal discs. As supported by the results presented in this thesis, FAK may be a good therapeutic target in cancer biology; however, in some contexts it may also behave as a tumour suppressor. Therefore, we conclude it will be necessary to identify the context of FAK activity before designing therapeutic strategies against FAK-expressing tumours.

Cancer is a group of diseases that affects almost every organ of the human body. A normal cell transforms into a cancer cell as a consequence of cumulative failures that alter diverse cellular processes such as cell proliferation, adhesion, migration, and cell death. Focal Adhesion Kinase (FAK) is a ubiquitous protein that is involved in all these cellular processes. Therefore, it is not surprising that FAK plays important roles in cancer; in fact, it has been linked to tumour progression or regression depending on the cellular and genetic context. We used Drosophila melanogaster as a model organism to study FAK’s duality in cancer. In this thesis we describe two novel roles of Drosophila FAK (FAK56): as a tumour suppressor within receptor tyrosine kinases (RTKs)-driven contexts, and as a tumour promoter by inhibiting cell death in nervous tissues. We investigated how FAK56 regulates signalling resulting from the overexpression of RTKs RET and EGFR. Our data indicated that FAK is a suppressor of RTKs in fly epithelia. This was also observed in human cancer cell lines, suggesting an evolutionary conserved mechanism. On the other hand, we found FAK56 prevented caspase-dependent cell death and uncovered a novel link between FAK56 and Relish, the Drosophila homologue of human NF-κB: Relish mutants suppressed FAK56 loss-induced cell death in the larval central nervous system and eye imaginal discs. As supported by the results presented in this thesis, FAK may be a good therapeutic target in cancer biology; however, in some contexts it may also behave as a tumour suppressor. Therefore, we conclude it will be necessary to identify the context of FAK activity before designing therapeutic strategies against FAK-expressing tumours.