Postdoctoral training - Genetics, Developmental and Cell Biology
Howard Hughes Medical Institute/Rutgers University (Advisor: Kenneth Irvine)
PhD - Human Genetics
University of Utah School of Medicine (Advisor: Carl Thummel)
DVM - Veterinary Medicine
Orissa University of Agriculture and Technology
Hippo pathway in cancer
The oncogenic transcriptional coactivators YAP and TAZ are the downstream effectors of the conserved Hippo signaling pathway and play a central role in cell proliferation, survival and fate specification. YAP/TAZ are frequently dysregulated in most human cancers, including, mesothelioma, uveal melanoma, lung, liver, breast and thyroid cancers, which exhibit increased YAP/TAZ activity. YAP promotes cancer cell proliferation, metastasis and chemo and immunotherapy resistance , and thus provides a critical control point for therapeutic intervention. We are taking a multipronged approach using computational chemistry, chemical biology and cell biology to develop inhibitors for YAP activity for treatment of various cancers.
Regulation of organ size control during development.
The Hippo signaling pathway plays a central role in organ size during embryonic development. We use the fruit fly, Drosophila melanogaster as a model organism to study how the Hippo signaling pathway and the cell adhesion molecules Dachsous and Fat play an important role in this process.
Gridnev A, Misra JR. Emerging Mechanisms of Growth and Patterning Regulation by Dachsous and Fat Protocadherins. Front Cell Dev Biol. 2022 Mar 16;10:842593. doi: 10.3389/fcell.2022.842593. PMID: 35372364; PMCID: PMC8967653.
Maity S, Gridnev A, Misra JR. Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers. Cancers (Basel). 2022 Feb 17;14(4):1029. doi: 10.3390/cancers14041029. PMID: 35205777; PMCID: PMC8869775.
Misra JR, Irvine KD. Early girl is a novel component of the Fat signaling pathway. PLoS Genet. 2019 Jan 30;15(1):e1007955. doi: 10.1371/journal.pgen.1007955.
Misra JR, Irvine KD. The Hippo Signaling Network and Its Biological Functions. Annu Rev Genet. 2018 Nov 23;52:65-87. doi: 10.1146/annurev-genet-120417-031621.
Misra JR, Irvine KD. Vamana Couples Fat Signaling to the Hippo Pathway. Dev Cell. 2016 Oct 24;39(2):254-266. doi: 10.1016/j.devcel.2016.09.017.
Misra JR, Lam G, Thummel CS. Constitutive activation of the Nrf2/Keap1 pathway in insecticide-resistant strains of Drosophila. Insect Biochem Mol Biol. 2013 Dec;43(12):1116-24. doi: 10.1016/j.ibmb.2013.09.005.
Misra JR, Horner MA, Lam G, Thummel CS. Transcriptional regulation of xenobiotic detoxification in Drosophila. Genes Dev. 2011 Sep 1;25(17):1796-806. doi: 10.1101/gad.17280911.
Kumar D, Kumar A, Misra JR, Chugh J, Sharma S, Hosur RV. 1H, 15N, 13C resonance assignment of folded and 8 M urea-denatured state of SUMO from Drosophila melanogaster. Biomol NMR Assign. 2008 Jun;2(1):13-5. doi: 10.1007/s12104-007-9072-6.
Kumar D, Misra JR, Kumar A, Chugh J, Sharma S, Hosur RV. NMR-derived solution structure of SUMO from Drosophila melanogaster (dSmt3). Proteins. 2009 Jun;75(4):1046-50. doi: 10.1002/prot.22389.
Chugh J, Sharma S, Kumar D, Misra JR, Hosur RV. Effect of a single point mutation on the stability, residual structure and dynamics in the denatured state of GED: relevance to self-assembly. Biophys Chem. 2008 Sep;137(1):13-8. doi: 10.1016/j.bpc.2008.06.005. - publications
Rising STARs award - University of Texas Board of Regents 
DeLill Nasser award - Genetic Society of America 
K99/R00 Pathway to Independence Award - National Institute of Health 
Rutgers University [2016–2019]
Howard Hughes Medical Institute/Rutgers University [2013–2016]
Hippo pathway in cancer and fibrosis.
The Hippo signaling pathway is evolutionarily conserved from fruit flies to humans and plays a central role in growth regulation. The downstream effector of this pathway YAP/TAZ plays a critical role in this process by regulating gene expression by associating withe the TEAD1-4 transcription factors. YAP/TAZ is frequently misregulated in most solid tissue cancers and provides a nodal point for treatment of various cancers. We take an interdisciplinary approach to understand how this pathway is deregulated in cancers and to develop inhibitors for treatment of cancers.
YAP/TAZ also plays a critical role in pulmonary fibrosis and YAP activity inhibitors have shown promising effect in treatment of this disease. So the YAP activity inhibitors we develop will also be useful for traetment of fibrosis.
Ongoing projects include:
1. To identify novel mechanisms by which YAP/TAZ gets deregulated in cancer.
2. To characterize the mechanism of transcriptional activation by YAP.
3. Development of small-molecule inhibitors of TEAD by using deep learning methods for virtual ligand screening.
4. Development of small-molecule inhibitors of TEAD by ultra large DNA-encoded library screening.
5. Development of Proteolysis Targeting Chimeras (PROTAC) for degrading TEAD.
6. Development of YAP-TEAD interaction inhibitors by screening custom protein-protein interaction inhibitor libraries.
Hippo pathway in organ size control.
Proper size and shape is required for optimal functioning of organs. In multicellular organisms, different tissues develop to a characteristic final size and shape, and maintain an optimal proportion to the body. Misregulation of growth and morphogenesis during development results in structural birth defects that last into adulthood and often lead to organ malfunction. The evolutionarily conserved Hippo signaling pathway plays a central role in organ size control and is associated with many cancers. The protocadherins, Dachsous (Ds) and Fat are conserved upstream regulators of Hippo signaling that play a key role in coordinating growth and morphogenesis. Ds and Fat restrict growth by activating Hippo signaling and influence morphogenesis by regulating planar cell polarity and oriented cell divisions. Consistently, mutations affecting this pathway result in a number of diseases affecting organ shape or size, such as Hennekam syndrome and Van Maldergem syndrome. However, the molecular mechanisms by which Fat signaling regulates growth and morphogenesis are not well understood. Our lab employs an interdisciplinary approach using Drosophila genetics, cell biology to study Ds-Fat signaling regulates Hippo signaling.
Ongoing projects include:
1. How is the spatial organization of the Ds-Fat signaling pathway established?
2. How Ds-Fat signaling regulates Hippo signaling?
3. How Fat signaling regulates organ shape?
Department of Biological Sciences
$1950,000 - NIH [2021/09–2026/08]
Regulation Of Tissue Growth And Morphogenesis By Fat Cadherins
~965000 - NIH [2016/08–2022/08]
Regulation of Organ size by Fat signaling