We recently made the surprising discovery that a TORC2 signaling network enforces the proportional relationship between cell size and growth rate in budding yeast. An important function of the TORC2 network is to modulate synthesis of ceramide lipids, which play roles in signaling. TORC2-dependent control of ceramide signaling strongly influences both cell size and growth rate. Thus, cells that cannot make ceramides fail to modulate their growth rate or size in response to changes in nutrients. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network. More recently, we discovered that nutrient-dependent signals are relayed to the TORC2 network via yeast homologs of the vertebrate LKB1 tumor suppressor kinase, which is required for cell size control in both yeast and vertebrates. Others have shown that TORC2 and ceramide-dependent signaling are strongly linked to cancer. Thus, we may be close to understanding why cancer cells have aberrant cell size control.

Discover novel ceramide-dependent signals that control cell growth and size.

Ceramide-dependent signals are a key output of the TORC2 network that relay feedback signals, as well as signals that control cell growth and size. However, little is known about ceramide-dependent signaling in yeast or vertebrates. It has been suggested that ceramides can generate or stabilize lipid microdomains that function as platforms for the recruitment of other signaling molecules. An alternative mechanism of ceramide signaling is through direct interaction with target proteins. However, only few specific ceramide binding proteins have been described to date.

We will use the exceptional tools available in yeast to discover mechanisms of ceramide-dependent signaling that are likely to be broadly relevant.

Define new LKB1-dependent signals that control cell growth and size.

We have previously shown that TORC2 is modulated in response to changes in carbon source. We found that the yeast homolog of LKB1, Elm1, relays nutrient signals to the TORC2 network. Elm1 influences TORC2 signaling independently of Snf1/AMPK, which points to the existence of a surprising new pathway that links LKB1 to TORC2 signaling. Elm1 is of particular interest because it was previously implicated in control of cell growth and size in yeast. Interestingly, loss of vertebrate LKB1 is also required for control of cell size, suggesting that its functions are conserved. Cancer cells increase glucose uptake to fulfill the biosynthetic demands of tumor growth. Thus, the discovery of a conserved mechanism that controls growth in response to nutrients will be relevant to cancer. A key next step will be to determine how Elm1 signals to the TORC2 network.

Discover how TORC2 activity is modulated by nutrients.

The discovery that TORC2 activity is modulated by nutrients adds a new dimension to TOR signaling. Little is known about how TORC2 is controlled. The specificity and activity of TOR complexes is thought to be controlled via changes in subunit composition and post-translational modification. Thus, analysis of how nutrients modulate the composition and modification of the TORC2 complex will yield new insight into signals that control cell growth.