In joint studies with his long-time collaborator, Phillip Hawkins, Leonard Stephens has made many outstanding contributions to knowledge of the variety and functions of inositol lipids and polyphosphates in eukaryotic cells. Early highlights were the mapping of new pathways of inositol phosphate synthesis, discovery of Ins(3,4,5,6)P4 and pyrophosphorylated derivatives of InsP6, and structural proof that cells contain 3-phosphorylated derivatives of phosphatidylinositol (PtdIns) — the analytical methods they developed for these studies are now standard. They established that PtdIns(4,5)P2 is the main substrate of receptor-controlled type 1 phosphoinositide 3-kinases (PI3Ks), thus identifying PtdIns(3,4,5)P3 as the key output signal from this reaction. They identified and isolated the GPCR-activated type 1B PI3K and, in a sustained body of work, defined its structure, explained its complex pattern of regulation, and proved its role in inflammatory events in vivo. They — in parallel with Dario Alessi — identified phosphoinositide-dependent kinase-1 as the PtdIns(3,4,5)P3-activated link between PI3K-1 activation and protein kinase B activation, a key pathway through which PtdIns(3,4,5)P3 formation regulates cell proliferation and survival.
Interest and expertise
Biochemistry and molecular cell biology
Biochemistry and molecular biology, Cell biology (incl molecular cell biology)