Our Big Question
Growth is one of the most fundamental features of life, and always occurs at the level of cells. Mechanisms that control the extent, location and rate of cell growth are essential for cell function and survival, and generate the myriad sizes and shapes of cells observed in nature. It is likely that cell growth is controlled by conserved mechanisms, since growth control would have been essential for the survival of the earliest cells. The goal of my work is to discover conserved, broadly relevant mechanisms that control cell growth and size in eukaryotic cells.
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.
• Kurt M. Schmoller, Michael C. Lanz, Jacob Kim, Mardo Koivomagi, Yimiao Qu, Chao Tang, Igor V. Kukhtevich, Robert Schneider, Fabian Rudolf, David M. Moreno, Mart. Aldea, Rafael Lucena and Jan M. Skotheim. “Whi5 is diluted and protein synthesis does not dramatically increase in pre-Start G1”. MOLECULAR BIOLOGY OF THE CELL. 2022 May 1;33(5):lt1. doi: 10.1091/mbc.E21-01-0029.
• Flor-Parra I, Sabido-Bozo S, Ikeda A, Hanaoka K, Funato K, Muñiz M, Lucena R*. “The ceramide synthase subunit Lac1 regulates cell growth and size in fission yeast”. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2022, 23(1), 303. *Corresponding author.
• Manzano-Lopez J, Rodriguez-Gallardo S, Sabido-Bozo S, Cortes-Gomez A, Perez-Linero AM, Lucena R, Cordones-Romero A, Lopez S, Aguilera-Romero A, Muñiz M “Crosslinking assay to study a specific cargo-coat interaction through a transmembrane receptor in the secretory pathway”. PLOS ONE (Accepted).
• Alcaide-Gavilan M, Lucena R, Banuelos S, and Kellogg DR. “Conserved Ark1-related kinases control TORC2 signaling”. MOLECULAR BIOLOGY OF THE CELL. Aug 15; 31(18): 2057-2069.
• Alcaide-Gavilan M+, Lucena R+*, Schubert K, Artiles K, Zapata J, Kellogg DR*. “A conserved Lkb1 signaling axis modulates TORC2 signaling in budding yeast”. GENETICS Sep; 210 (1):155-170. +Co-first authors, *Corresponding authors.
• Flor-Parra I, Iglesias AB, Salas-Pino S, Lucena R., Jimenez J, Daga RR. “Virtual nuclear envelope breakdown controls spindle disassembly in fission yeast”. CELL REPORTS Apr 24; 23(4):933-41.
• Qiu C., Yi Y., Lucena R., Wu M., Sun J., Wang X., Jin Q., Wang Y. “F-Box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast”. JOURNAL OF CELL SCIENCE. Feb 2; 131(3)
• Lucena R*, Alcaide-Gavilan M*, Schubert K, He M, Domnauer M, Marquer C, Klose C, Surma MA, Kellogg DR. “Cell size and growth rate are modulated by TORC2-dependent signals”. CURRENT BIOLOGY. Jan 22;28(2) 196-210. *Co-first authors
• Vadia S, Tse JL, Lucena R, Yang Z, Kellogg DR, Wang JD, Levin PA. “Fatty acid availability sets cell envelope capacity and dictates microbial cell size”. CURRENT BIOLOGY. Jun 19; 27(12): 1757- 1767.
• Lucena R*+, Alcaide-Gavilan M+, Anastasia SD, Kellogg DR. “Wee1 and Cdc25 are controlled by conserved PP2A-dependent mechanisms in fission yeast”. CELL CYCLE. Mar 4; 16(5): 428-435. +Co-first authors. *Corresponding author
• Lucena R, Dephoure N, Gygi SP, Kellogg DR, Tallada VA, Daga RR, Jimenez J. “Nucleocytoplasmic transport in the midzone membrane domain controls yeast mitotic spindle disassembly”. THE JOURNAL OF CELL BIOLOGY. May 11; 209(3):387-402
• Parnell EJ, Yu Y, Lucena R, Yoon Y, Bai L, Kellogg DR, Stillman DJ. “The Rts1 regulatory subunit of PP2A phosphatase controls expression of the HO endonuclease via localization of the Ace2 transcription factor”. THE JOURNAL OF BIOLOGICAL CHEMISTRY. Dec 19; 289(51):35431
• McGrath DA, Balog ER, Koivomagi M, Lucena R, Mai MV, Hirschi A, Kellogg DR, Loog M, Rubin SM. “Cks confers specificity to phosphorylation-dependent CDK signaling pathways”. NATURE STRUCTURAL & MOLECULAR BIOLOGY. Dec; 20(12):1407-14
Rafael Lucena (Principal Investigator)
B.S. Biology (University of Seville)
PhD in Biotechnology (CABD, University Pablo de Olavide)
PostDoc in Molecular, Cell & Dev. Biology (University of California, Santa Cruz)
Nacho Quesada (Master’s Student)
Eugenia Cabezas (Undergrad Student)
Ana Maria Serrano (Undergrad Student)
Andrea del Valle (Undergrad Student)
Our Contact Info
The lab is at the Department of Cell Biology, University of Seville. We are located on the 4th floor of the Green building in the Reina Mercedes Campus, Seville, Spain.
We are excited about new incorporations! If funding is not available, we could discuss some options.
Department of Cell Biology
School of Biology
University of Seville
Av Reina Mercedes 6