This grant concerns two largely unresolved mechanisms in cell biology: morphogenesis and size control. Cell morphogenesis is largely determined by the actin cytoskeleton, which must interact with complex signaling and membrane processes. Previously, we found that one set of circuits (the N-WASP pathway) involves membranes in two steps through the small GTP-binding signaling molecule, Cdc42, and most interestingly through a protein called toca-1, which is thought to respond to membrane curvature. One of our aims is to understand how this membrane/actin machine functions in morphogenesis.
A second aim i s to understand another membrane-actin complex, called the WAVE complex, which is involved in assembling actin in broad cell extensions. The major task here is to understand how the WAVE complex is regulated and interacts with membranes. In the third section, we ask how actin assembles into exploratory needle-like cell protuberances, called filopodia, important in a vast variety of cell functions from hearing to neuronal pathfinding. We have succeeded in reconstituting filopodia-like structures on flat lipid membranes in vitro in cell extracts, laying open all of the unresolved questions of composition, organization, and regulation. The second major section concerns the regulation of cell size, the process that balances cell division and growth, where outside of yeast little is known. We propose ways to measure the growth of normal and tumor cells using novel means of quantitative mass spectrometry. For specific molecular clues, we turn to a system where this process is interrupted and resumed, embryonic cell divisions. We search for the signals involved in the resumption of growth in frog and nematode embryos, using biochemical and genetic tools. Control of cell growth and cell shape are both fundamental to understanding many pathological conditions, in cancer and embryology.
|Lee, Ho-Joon; Jedrychowski, Mark P; Vinayagam, Arunachalam et al. (2017) Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation. Cell Rep 20:721-736|
|Lu, Ying; Wu, Jiayi; Dong, Yuanchen et al. (2017) Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle. Mol Cell 67:322-333.e6|
|Brown, Nicholas G; VanderLinden, Ryan; Watson, Edmond R et al. (2016) Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C. Cell 165:1440-1453|
|Lee, Byung-Hoon; Lu, Ying; Prado, Miguel A et al. (2016) USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532:398-401|
|Chen, Shuobing; Wu, Jiayi; Lu, Ying et al. (2016) Structural basis for dynamic regulation of the human 26S proteasome. Proc Natl Acad Sci U S A 113:12991-12996|
|Ginzberg, Miriam B; Kafri, Ran; Kirschner, Marc (2015) Cell biology. On being the right (cell) size. Science 348:1245075|
|Klein, Allon M; Mazutis, Linas; Akartuna, Ilke et al. (2015) Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161:1187-1201|
|Li, Victor C; Kirschner, Marc W (2014) Molecular ties between the cell cycle and differentiation in embryonic stem cells. Proc Natl Acad Sci U S A 111:9503-8|
|Zhao, Rui; Deibler, Richard W; Lerou, Paul H et al. (2014) A nontranscriptional role for Oct4 in the regulation of mitotic entry. Proc Natl Acad Sci U S A 111:15768-73|
|Ortiz-Meoz, Rodrigo F; Merbl, Yifat; Kirschner, Marc W et al. (2014) Microarray discovery of new OGT substrates: the medulloblastoma oncogene OTX2 is O-GlcNAcylated. J Am Chem Soc 136:4845-8|
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