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.
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|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|
|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|
|Klein, Allon M; Mazutis, Linas; Akartuna, Ilke et al. (2015) Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161:1187-201|
|Ginzberg, Miriam B; Kafri, Ran; Kirschner, Marc (2015) Cell biology. On being the right (cell) size. Science 348:1245075|
|Satoh, Noriyuki; Tagawa, Kunifumi; Lowe, Christopher J et al. (2014) On a possible evolutionary link of the stomochord of hemichordates to pharyngeal organs of chordates. Genesis 52:925-34|
|Xiong, Fengzhu; Ma, Wenzhe; Hiscock, Tom W et al. (2014) Interplay of cell shape and division orientation promotes robust morphogenesis of developing epithelia. Cell 159:415-27|
|Slenn, Tamara J; Morris, Benjamin; Havens, Courtney G et al. (2014) Thymine DNA glycosylase is a CRL4Cdt2 substrate. J Biol Chem 289:23043-55|
|Gujral, Taranjit Singh; Peshkin, Leonid; Kirschner, Marc W (2014) Exploiting polypharmacology for drug target deconvolution. Proc Natl Acad Sci U S A 111:5048-53|
|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|
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