RESEARCH
Evolutionary rewiring of cell signaling
Every cell needs to sense and process information through signaling. Intriguingly, there is a remarkable degree of repurposing (rewiring of cellular inputs/outputs) when comparing homologous signaling pathways or components across organisms. For example, while Ras regulates the MAPK pathway in animals in response to growth factors, in budding yeast it regulates adenylate cyclase in response to nutrients. Similarly, while the Hippo pathway regulates tissue growth in animals, its counterpart in budding yeast, known as the mitotic exit network (MEN), safeguards the fidelity of mitosis. Furthermore, genetic interactions of signaling proteins, such as kinases, are less conserved than average, suggesting that rewiring of cell signaling is widespread and is likely a key source of evolutionary innovations. Despite the prevalence and importance of this phenomenon, we lack a mechanistic understanding on how signaling rewiring occurs evolutionarily, especially for signaling pathways that control essential cellular functions.
We are addressing this fundamental question using the MEN/Hippo pathway as a model system. The MEN/Hippo pathway is an ancient signaling pathway in eukaryotes with diverse functions. In addition to budding yeast and animals, this pathway has been shown to regulate cytokinesis/septation in the fission yeast S. pombe and the filamentous fungus A. gossypii, G1/S transition in the cucumber anthracnose fungus C. orbiculare, nuclear envelope breakdown in the corn smut U. maydis, phagocytosis in the slime mold D. discoideum, and tissue patterning and reproduction in plants (A. thaliana). By uncovering how this ancient signaling pathway diverged from its ancestral state to control different functions in extant organisms, our research will not only shed light on how rewiring of cell signaling occurs and gives rise to evolutionary innovations, but also provide insights for human diseases such as cancer where signaling rewiring is widely observed and can underlie resistance to treatment.
The mitotic exit network (MEN)
The MEN is a GTPase-kinase signaling cascade that controls a critical cell cycle transition from mitosis to G1 known as exit from mitosis in budding yeast. By integrating multiple inputs including mitotic spindle position, the MEN ensures that exit from mitosis only occurs after successful genome partitioning between mother and daughter cell/bud. We recently discovered that the MEN senses and converts spatial information inside the cell (spindle position) into chemical signals (activation of MEN kinases) through a noncanonical GTPase signaling mechanism where the MEN GTPase Tem1 does not function as a molecular switch like the classic Ras GTPase (Zhou et al, in preparation). We are now dissecting the logic of signal transduction in this noncanonical GTPase signaling pathway and exploring its evolutionary implications.
Rewiring in different cellular contexts
One attractive feature making the MEN an excellent model to study the mechanism of signaling rewiring is that in addition to being repurposed across different organisms, within budding yeast the pathway has already been rewired for meiosis. During mitosis, the MEN responds to spindle position via its GTPase Tem1, whereas in meiosis, where budding is suppressed and thus there is no need to sense spindle position, Tem1, although present, is not required for MEN function. How do the same proteins take different cellular inputs/outputs in mitosis versus meiosis? What are the input signals for the pathway in meiosis? Using a combination of genetics, proteomics, quantitative microscopy, and biochemistry, we are investigating how the pathway is rewired between mitosis and meiosis. Elucidating how the pathway is differentially regulated in mitosis versus meiosis will not only provide insights on how the wiring of signaling pathways can be altered in different cellular contexts, but also offer clues to how selection might repurpose the MEN during evolution.
Rewiring across organisms
The filamentous fungus Ashbya gossypii, a plant pathogen, is a close relative of S. cerevisiae but grows as multinucleate hyphae where nuclear division occurs asynchronously and is uncoupled from cytokinesis. The lack of spatial and temporal constraints of mitosis, which are key inputs for the MEN in S. cerevisiae, and high degree of gene homology make A. gossypii an excellent model to study the evolutionary rewiring of MEN signaling.
The human pathogen, Cryptococcus neoformans, divides by budding, but unlike S. cerevisiae it undergoes a semi-open mitosis with chromosomes segregating from the bud to mother cell, providing an attractive comparative model to study evolution of mitosis and the MEN. Furthermore, C. neoformans undergoes an unusual morphogenetic switch from haploid yeast to giant, highly polyploid cells (“Titan cells”) in the host lung. How the cell cycle and the MEN are potentially altered to enable this transition is not understood, providing another excellent model to study rewiring in different cellular contexts.