My research focuses on understanding how transforming growth factor beta (TGF-beta) signaling controls a wide spectrum of molecular and cellular effects ranging from proliferation to differentiation and cell motility. While gene regulation is the primary mode of signal transduction, often occurring in a highly context-specific manner, our long-term goals include characterizing novel mechanisms by which the canonical effectors, namely the nuclear shuttling SMAD transcription factors and TGF-beta-activated kinase 1 (TAK1), directly modulate cellular activities.
Along with traditional biochemical, biophysical and cellular approaches, we have employed mass spectrometry/proteomics as a key strategy to identify new binding partners and their transcription-independent roles across cell types. We previously discovered that transcriptionally “inactive” SMAD proteins residing in the cytoplasm can influence mitochondrial dynamics through interaction with mitofusin 2 (MFN2), a GTPase critical for mitochondrial fusion in mammalian systems. We found that SMADs do not act alone, but rather as a protein scaffold complex with RIN1 (guanine nucleotide exchange factor) to enhance the MFN2 GTP-binding properties and promote mitofusion.
Likewise through similar methods, we recently characterized new protein interactions between TAK1 and a subset of microtubule modifying enzymes. We are interested in learning how these interactions control microtubule functions including their mechanical stability as well as cellular transport of protein cargo. Collectively, these findings represent major new facets of TGF-beta biology and directions for the lab as we explore how disease-causing mutations impact their functional interactions in cancer, metabolic and neurologic conditions.
Varadarj A, Jenkins LM, Singh P, Chanda A, Snider J, Lee NY, Amsalem-Zafran AR, Ehrlich M, Henis YI, Mythreye K. TGF-beta triggers rapid fibrillogenesis via novel TRII dependent fibronectin trafficking mechanism. Mol Biol Cell. 28(9):1195-1207 (2017)
Pan CC, Shah N, Kumar S, Wheeler SE, Cinti J, Hoyt DG, Beattie CE, An M, Mythreye K, Rakotondraibe LH, Lee NY. Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy. Oncotarget. 21:8(8):12675-12685 (2017)
Jenkins L, Varadaraj A, Singh P, Lee NY, Shah S, Flores H, O’Connell K, Mythreye K. Altering the proteoglycan state of Betaglycan modulates canonical Wnt/beta-catenin signaling. J Biol Chem. 291(49): 25716-25728 (2016)
Kumar S, Pan CC, Shah N, Wheeler SE, Hoyt KR, Hempel N, Mythreye K, Lee NY. Activation of mitofusin2 by Smad2-RIN1 complex during mitochondrial fusion. Molecular Cell. 62(4):520-31. (2016)
Pan CC, Kumar S, Shah N, Bloodworth JC, Hawinkels LJ, Mythreye K, Hoyt DG, Lee NY. Endoglin regulation of Smad2 function mediates beclin1 expression and endothelial autophagy. J Biol Chem. 12:290(24):14884-92. (2015)
Pan CC, Kumar S, Shah N, Hoyt DG, Hawinkels LJ, Mythreye K, Lee NY. Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis. J Biol Chem. 289(37):25486-96. (2014)
Kumar S, Pan CC, Bloodworth JC, Nixon A, Theuer C, Hoyt DG, Lee NY. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-eta signaling. Oncogene. 33(30): 3970-9. (2013)