Discoveries in Human Biology Through Kinase Signaling

Kinases are signaling proteins that are involved in many different cellular processes. There are over 500 different kinases to accomplish these various tasks. Abnormal kinase signaling can lead to severe disease outcomes. Studying these disruptions have led to fundamental discoveries about human and cellular biology. Chapter 1 introduces a number of cases in both cancer and infectious disease where kinase signaling is disrupted. The subsequent studies used to elucidate why these disruptions occur have helped advance our current knowledge of human biology. In Chapter 2 I describe about some of our studies with eukaryotic-like ser/thr protein kinases used as effector proteins by the bacteria Legionella pneumophila, the causative agent of Legionnaires’ disease. This chapter explores in vitro and in vivo assays to characterize four of the known and conserved effector kinases from Legionella. Chapter 3 takes a comprehensive look at Legionella kinase 4 (LegK4), one of the effector kinases that showed an interesting Golgi fragmentation phenotype. We discovered that LegK4 targets host Hsp70, reduced the chaperone’s refolding activity, and subsequently reduced global translation of the host cell. Further work showed that phosphorylation of Hsp70 by LegK4 increases the amount of the chaperone present on highly translating polysomes. Chapter 4 reviews the available kinase substrate identification techniques, and explain how we used one of them to explore substrates of Protein Kinase A (PKA) in cell lines of small cell lung cancer. While many substrates were found, a general theme emerged where a number of the direct targets of PKA were involved in cell cycle and cell proliferation. Follow-up experiments performed by our collaborators showed that these results align well with a global phosphoproteomic analysis carried out for PKA in a small cell lung cancer setting. All of these examples show kinase signaling that helped to inform us about new human biology