The connection between metabolism and cellular behaviors

We have a growing but incomplete understanding of the mechanisms whereby the body senses its nutrient status and responds to adapt cellular and organismal behavior accordingly. These discoveries support the notion that the metabolic program of stem cells is not a byproduct of their environments or a passive feature of their cell biology, but rather a driving force that influences their fate and function.

 

Metabolic underpinnings of cancer and stem cells

Our discovery of the Mitochondrial Pyruvate Carrier (MPC) has led to the initiation of a significant effort in the lab to understand the fundamental metabolic underpinnings of cancer and stem cells. Modulation of pyruvate metabolism via chemical or genetic manipulation of the MPC has profound effects on intestinal stem cell function and proliferation as well as on cancer metabolism, supporting the idea that metabolism is not merely a by-product but rather an intrinsic driving force of cell fate. We are currently extending these studies using mouse models of human diseases including colon cancer and heart failure.

 
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MIDAS

Small molecule allostery modifies protein function but is not easily discoverable. We have developed an experimental platform - mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) - that enables the identification of physiologically relevant, low-affinity metabolite-protein interactions using unmodified proteins and complex mixtures of unmodified metabolites. Our latest iteration of MIDAS enables high-throughput identification of the allesterome of purified proteins to uncover novel aspects of biology.

 
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PASK

PAS domain containing protein kinase (Pask) is an evolutionarily conserved, nutrient-sensing serine/threonine protein kinase implicated in energy homeostasis and metabolic regulation across eukaryotic species. We recently described an unexpected role for Pask in regulating the differentiation of stem and progenitor cells into neuronal, adipocytes, and myocytes lineages. Subsequent work has shown that Pask is an interacting partner and a direct substrate of mTORC1, and that is a necessary mediator of the alterations in epigenetic markers that drive muscle cell differentiation in response to nutrient and hormonal signals.