Julian Downward’s work on the Ras GTPase has made seminal contributions to our understanding of how cellular signal transduction pathways are subverted in oncogenic transformation. His work provided the first demonstration that GTP-loading on Ras, which is commonly mutationally activated in human tumours, is normally regulated in response to extracellular factors; he went on to characterise growth factor receptor complexes mediating Ras nucleotide exchange, and to demonstrate that GTP-bound Ras binds to and activates the Raf kinase, which controls the MAP kinase pathway. Julian was first to demonstrate that phosphoinositide 3-kinase (PI 3-kinase) is also a Ras effector, important in regulation of apoptosis. He showed that transformation by Ras requires interaction with multiple effectors, which contribute differentially to cell cycle progression, cytoskeletal regulation and apoptosis. His more recent work has established that both cell matrix and cell–cell interaction activate the PI 3-kinase/PKB pathway, and thereby prevent programmed cell death, and that it is activation of this pathway by oncogenic Ras that allows anchorage-independent growth of transformed cells.
Senior Group Leader, Institute of Cancer Research , Oncogene Biology Laboratory, The Francis Crick Institute
Interest and expertise
Biochemistry and molecular cell biology
Biochemistry and molecular biology, Cell biology (incl molecular cell biology)
Oncogenes, Basic cancer research, EGFR signaling, Ras signaling, cancer models