This paper shows that the central growth regulator mTORC1 determines the physical properties of the cytoplasm! By modulating the concentration of ribosomes through production and autophagy, the rates of diffusion of everything in the cell that is >15 nm diameter can be varied 2-fold in yeast and 20% in humans. Therefore, all of the second-order rate constants for any reasonably-sized complex in the cell  is not constant . Also, phase separation is substantially regulated by this crowding regulation.

This paper shows that the central growth regulator mTORC1 determines the physical properties of the cytoplasm! By modulating the concentration of ribosomes through production and autophagy, the rates of diffusion of everything in the cell that is >15 nm diameter can be varied 2-fold in yeast and 20% in humans. Therefore, all of the second-order rate constants for any reasonably-sized complex in the cell is not constant. Also, phase separation is substantially regulated by this crowding regulation.

 What are polyglutamine repeats (polyQs) for? These mysterious amino acid repeats cause neurodegenerative diseases including Huntington's Chorea, but in some organisms, 10% of the proteome has these repeats. Here we discover a new function for polyQs: A domain containing around 100 glutamines in the SWI/SNF chromatin remodeling acts as a pH sensor and helps reprogram transcriptional in response to stress. So why the picture of a terrifying spider? See the last figure to find out :)

What are polyglutamine repeats (polyQs) for? These mysterious amino acid repeats cause neurodegenerative diseases including Huntington's Chorea, but in some organisms, 10% of the proteome has these repeats. Here we discover a new function for polyQs: A domain containing around 100 glutamines in the SWI/SNF chromatin remodeling acts as a pH sensor and helps reprogram transcriptional in response to stress. So why the picture of a terrifying spider? See the last figure to find out :)

 We know quite a bit about how cells sense tensile stresses, but almost nothing about how cells detect and respond to mechanical compressive stress (pressure). All of the cells in our body are under pressure. We should probably figure this out. This paper describes the SMuSh pathway, required for cells to survive when growing under pressure! At the top of the pathway is a mucin. Mucins are frequently misregulated in cancer. We think these sensors will play an important role in the adaptation of cancer to new mechanical conditions.

We know quite a bit about how cells sense tensile stresses, but almost nothing about how cells detect and respond to mechanical compressive stress (pressure). All of the cells in our body are under pressure. We should probably figure this out. This paper describes the SMuSh pathway, required for cells to survive when growing under pressure! At the top of the pathway is a mucin. Mucins are frequently misregulated in cancer. We think these sensors will play an important role in the adaptation of cancer to new mechanical conditions.

Peer reviewed papers

Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity Howard, C., Hanson-Smith, V., Kennedy, K.J., Miller, C.J., Lou, H.J., Johnson, A.D., Turk, B., and Holt, L.J. (2014). Elife 3.

 Amazingly, we can reconstruct and resurrect kinases from >2 billion years ago and determine their specificity! The deep ancestors of Cdk1, MAP kinases and Ime2 reveal that the gatekeeper residue helps determine specificity. This paper also suggests that kinase networks can tolerate new information, thus providing a pathway for dramatic rewiring of the cell's circuitry.

Amazingly, we can reconstruct and resurrect kinases from >2 billion years ago and determine their specificity! The deep ancestors of Cdk1, MAP kinases and Ime2 reveal that the gatekeeper residue helps determine specificity. This paper also suggests that kinase networks can tolerate new information, thus providing a pathway for dramatic rewiring of the cell's circuitry.

Global Analysis of Cdk1 Substrate Phosphorylation Sites Provides Insights into Evolution. Holt, L.J., Tuch, B., Villen, J., Johnson, A., Gygi, S., and Morgan, D. (2009) Science 325, 1682.

 We combined the  "Shokat" analog-sensitive kinase approach  with SILAC quantitative mass spectrometry (with the  Gygi lab ) to discover >300 Cdk1 substrates in  S. cerevisiae . Evolutionary analysis revealed that these sites, while often conserved for >1 billion years (bottom), are very rarely conserved in terms of their precise position (top). This work suggests that phosphorylation networks are quite evolvable. Biological information systems can change readily to adapt to new challenges.

We combined the "Shokat" analog-sensitive kinase approach with SILAC quantitative mass spectrometry (with the Gygi lab) to discover >300 Cdk1 substrates in S. cerevisiae. Evolutionary analysis revealed that these sites, while often conserved for >1 billion years (bottom), are very rarely conserved in terms of their precise position (top). This work suggests that phosphorylation networks are quite evolvable. Biological information systems can change readily to adapt to new challenges.

Positive feedback sharpens the anaphase switch. Holt, L.J., Krutchinsky, A.N., and Morgan, D.O. (2008). Nature 454, 353–357.

 Positive feedback can generate switch-like behaviors where systems abruptly and irreversibly transition from one state to another ( bistability ). We found a positive feedback look involving Cdk1, Cdc14, Securin, Separase and the Anaphase Promoting Complex (some of the tastiest spices in the soup of regulators that is the cell cycle). This feedback loop ensures synchronous chromosome segregation at anaphase onset and improves the fidelity of cell division. 

Positive feedback can generate switch-like behaviors where systems abruptly and irreversibly transition from one state to another (bistability). We found a positive feedback look involving Cdk1, Cdc14, Securin, Separase and the Anaphase Promoting Complex (some of the tastiest spices in the soup of regulators that is the cell cycle). This feedback loop ensures synchronous chromosome segregation at anaphase onset and improves the fidelity of cell division.