Molecular Regulation Laboratory
Research Program Overview:
The Molecular Regulation Laboratory is dedicated to exploring molecular basis of organismal homeostasis through the essential cellular processes such as ubiquitination and cell death. Given the discovery nature of our research program our work influences many areas of pathophysiology. Over the years we have made pioneering contributions to biomedical research. For example, our team discovered one of the first mammalian cell death proteases (caspase-2), identified and characterized key components of the cell death machinery, demonstrated how cell death is regulated by caspases, and described the developmental cell death modality that requires autophagy. We also discovered one of the first and evolutionarily most conserved family of ubiquitin ligases (the NEDD4 family), identified a ubiquitin-like protein NEDD8 that led to the discovery of protein modification pathway now known as Neddylation, and identified NDFIP1 and NDFIP2 as adaptors/regulators of NEDD4 family members. Much of the work in our laboratory is based on our own discoveries as we continue to explore the molecular mechanisms, regulation and physiological functions of cell death and ubiquitination, and how their dysregulation results in a multitude of diseases, including cancer, inflammation and kidney injury.
Current Research Projects:
- Study of caspases in cell death, metabolism and age-related cancer
- Non-apoptotic cell death modalities, including autophagy-dependent cell death
- Ubiquitin ligases and their adaptors in physiology and disease
- How ubiquitination regulates the biogenesis and function of extracellular vesicles
Selected Recent Publications:
- Farooq AU, Gembus K, Sandow JJ, Webb A, Mathivanan S, Manning JA, Shah SS, Foot NJ, Kumar S (2022) K-29 linked ubiquitination of Arrdc4 regulates its function in extracellular vesicle biogenesis. J Extracell Vesicles. 11: e12188.
- Lim Y, De Bellis D, Sandow JJ, Capalbo L, D’Avino PP, Murphy JM, Webb AI, Dorstyn L, Kumar S (2021) Phosphorylation by Aurora B kinase regulates caspase-2 activity and function. Cell Death Differ. 28: 349–366.
- Manning JA, Shah SS, Nikolic A, Henshall TL, Khew-Goodall Y, Kumar S (2021) The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease. Cell Death Dis. 12: 398.
- Shah SS, Kumar S (2021) Adaptors as the regulators of HECT ubiquitin ligases. Cell Death Differ. 28: 455-472.
- Foot NJ, Gonzalez M, Gembus K, Fonseka P, Sandow JJ, Nguyen TT, Tran D, Webb AI, Mathivanan S, Robker RL, Kumar S (2021) Arrdc4-dependent extracellular vesicle biogenesis is required for sperm maturation. J Extracell Vesicles. 10: e12113.
- Manning JA, Shah SS, Henshall TL, Nikolic A, Finnie J, Kumar S (2020) Dietary sodium modulates nephropathy in Nedd4-2-deficient mice. Cell Death Differ. 27: 1832–1843.
- Denton D, Kumar S (2019) Autophagy-dependent cell death. Cell Death Differ. 26: 605–616.
- Denton D, Xu T, Dayan S, Nicolson S, Kumar S (2019) Dpp regulates autophagy-dependent midgut removal and signals to block ecdysone production. Cell Death Differ. 26: 763–778.
- Dawar S, Lim Y, Puccini J, White M, Thomas P, Bouchier-Hays L, Green DR, Dorstyn L, Kumar S (2017) Caspase-2 mediated cell death is required for deleting aneuploid cells. Oncogene 36: 2704-2714.
- Foot N, Henshall T, Kumar S (2017) Ubiquitination and the regulation of membrane proteins. Physiological Reviews. 97: 253-281.
- Yip KH, Kolesnikoff N, Hauschild N, Biggs L, Lopez AF, Galli SJ, *Kumar S, *Grimbaldeston M (2016) The Nedd4-2-Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation. Nature Communications 7: 13198 (*senior authors)
- Shalini S, Dorstyn L, Dawar S, Kumar S (2015) Old, new and emerging functions of caspases. Cell Death Differ. 22: 526-539.
- Puccini J, Shalini S, Voss AK, Gatei M, Wilson CH, Hiwase DK, Lavin MF, Dorstyn L, Kumar S (2013) Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice. Proc Natl Acad Sci USA 110: 19920-
- Boase NA, Rychkov, GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S (2011) Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nature Communications 2: 287.