07.03.2013
Winner of 2013 FAOBMB Award for Research Excellence: Professor Sharad Kumar (Australia)
The winner of 2013 FAOBMB Award for Research Excellence is Professor Sharad Kumar from Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Professor Sharad Kumar
Molecular Regulation Laboratory, Centre for Cancer Biology, SA Pathology, Adelaide, Australia
Sharad Kumar is leading scientist in his disciplines whose original research has had a major impact in biochemistry, molecular biology and cell biology. His discoveries have resulted in seminal and fundamental advancements in two key fields: cell death and protein modification through ubiquitination.
Cell death is a major mechanism for deleting unwanted cells in metazoans. Caspases are cysteine proteases that are essential for the execution of cell death by apoptosis. As the discoverer of the one of the first mammalian caspases, Sharad made a critical contribution to the evolution of the cell death field. In 1991 Sharad discovered a series of genes highly expressed in neural precursor cells, which he named Nedds (Neural precursor cell-expressed developmentally downregulated). He discovered that Nedd2 (caspase-2) was one of the first mammalian caspases. His laboratory remains a key caspase groups world-wide, publishing seminal work on caspase biochemistry, substrates, mechanism of activation and function, and has recently discovered unexpected roles for caspase-2 in tumour suppression and aging.
In addition to work on mammalian caspases, Sharad’s laboratory also discovered and characterized a major part of the insect cell death machinery through the discovered of four of the seven caspases and both Bcl-2 homologues in Drosophila. He is now a leading scientist in this field with pioneering contributions to the understanding of hormone-regulated transcriptional control of developmentally programmed cell death (PCD). His laboratory went on to delineate the key components of the cell death program and the mechanisms that control spatial and temporal regulation of PCD during animal development.
In collaborative work Sharad’s laboratory recently defined an unusual mode of developmental PCD involving autophagy. It was found that the canonical caspase-mediated pathway is not required for the larval midgut PCD. By contrast, midgut PCD was suppressed by the loss of autophagy and by enhanced growth signalling, indicating that autophagy and growth arrest (not apoptosis) are essential for midgut PCD, providing the first in vivo evidence for caspase-independent PCD that requires autophagy. Autophagic PCD is now a major research interest of Sharad’s group.
Sharad’s laboratory also carried out original work on Nedd1, Nedd4, Nedd5 (Sept2) and Nedd8. Based on its conservation from yeast to man and its similarity to ubiquitin in 1993 he proposed that Nedd8 would be involved in a protein modification system similar to ubiquitination. Indeed, subsequent research from various groups found that Nedd8 is involved in a protein modification system, now commonly known as Neddylation, a critical process that regulates ubiquitination by cullin E3s.
The other main focus of Sharad’s research is on Nedd4 family of ubiquitin ligases (E3s). Nedd4 is the prototypic member of the family and was one of the first discovered HECT ligases. This unique E3 family established a new paradigm in the regulation of membrane proteins, including ion channels, receptors, transporters and associated signalling pathways. Among several key discoveries, Sharad team and their collaborators found that Nedd4 is essential for IGF-1 and insulin signalling. The Nedd4 deficiency results in a potent inhibition of the growth signalling cascade and embryonic lethality. Research from other groups has found that Nedd4 is also essential for the development of vascular system and the CNS, and plays a key role in virus budding and in protein trafficking.
Sharad’s group and collaborators established that a close relative of Nedd4, Nedd4-2, is an essential regulator of several ion channels, including epithelial (ENaC) and voltage gated (NaV) Na+ channels. Nedd4-2 is thus involved in maintaining Na+ homeostasis, blood pressure and lung fluid clearance in newborn animals. Consistent with this Nedd4-2-deficient mice have deregulated NaVs, increased ENaC expression in lungs resulting in premature fluid clearance, lung collapse and perinatal death of most animals. Human NEDD4-2 polymorphisms are now known to be associated with familial hypertension.
Finally, Sharad laboratory discovered N4WBPs (now called Ndfip1 and Ndfip2) in a screen for proteins that bind WW domains of Nedd4. Ndfip1 and Ndfip2 are adaptors that recruit Nedd4 E3s to some of their substrates. His group found that Ndfip1 is an essential regulator of the iron transporter DMT1 and iron homeostasis. Given that Ndfips impart specificity to ubiquitination, and they are now known to be involved in multiple pathophysiological conditions (e.g. iron overload, anaemia, immunity and inflammation), these proteins hold much promise as clinically useful drug targets.
