Tem1

Tem1. It is a crucial GTPase protein and a core component of the mitotic exit network (MEN) in the budding yeast Saccharomyces cerevisiae. Functioning as a molecular switch, it regulates the transition from mitosis to G1 phase by controlling the inactivation of Cdk1-cyclin B complexes. Its activity is spatially regulated at the spindle pole body and is essential for coordinating cytokinesis with the completion of chromosome segregation.

Function and role in the cell cycle

Tem1 acts as the initiating GTPase for the mitotic exit network, a signaling cascade essential for exiting mitosis. It becomes activated only when the anaphase spindle is properly aligned between the mother cell and the bud, ensuring daughter cells inherit a complete set of chromosomes. This spatial control links the completion of nuclear migration to cell cycle progression, preventing premature mitotic exit and genomic instability. Once activated, Tem1-GTP triggers the MEN pathway, leading to the release of the Cdc14 phosphatase from the nucleolus, which is the definitive step for cyclin degradation and Cdk1 inactivation.

Structure and regulation

The protein structure of Tem1 includes characteristic G domain motifs responsible for GTP binding and hydrolysis, similar to other small GTPases like Ras and Ran. Its activity is tightly controlled by a GAP (GTPase-activating protein) complex consisting of Bub2 and Bfa1, which promotes the inactive GDP-bound state, and a putative GEF (guanine nucleotide exchange factor), such as the Lte1 protein, which may facilitate activation. Localization to the spindle pole body is critical, with regulation influenced by the kinetochore-based spindle assembly checkpoint and the RENT complex to ensure precise timing.

Interaction with the mitotic exit network

Within the mitotic exit network, active Tem1-GTP directly binds and activates the Cdc15 kinase at the spindle pole body. This interaction initiates a phosphorylation cascade that ultimately mobilizes the Cdc14 phosphatase from the nucleolus. The released Cdc14 then dephosphorylates key targets, including the Cdk1 inhibitor Sic1 and cyclin-Cdk substrates, driving the cell into G1 phase. This pathway is analogous to the Hippo pathway in metazoans and is inhibited by the Bub2-Bfa1 complex until correct spindle orientation is achieved.

Homologs and evolutionary conservation

Tem1 is the functional ortholog of the Ras-superfamily GTPase Rit in higher eukaryotes, though its most direct counterpart in the cell cycle context is found within the conserved Ras-association domain family. The core mitotic exit network signaling logic is evolutionarily conserved, with the Hippo pathway components Mob1 and Dbf2/Dbf20 having direct homologs in humans, such as Mob1 and LATS1/LATS2. Studies in fission yeast (Schizosaccharomyces pombe) have identified the analogous septation initiation network (SIN), where the GTPase Spg1 performs a role similar to Tem1.

Clinical significance and research

Dysregulation of the mitotic exit network and its regulators is implicated in cancer, particularly due to its role in ensuring faithful chromosome segregation and preventing aneuploidy. Research on Tem1 has provided fundamental insights into cell cycle checkpoints, asymmetric cell division, and the origins of chromosomal instability. Its regulatory principles inform studies on analogous pathways in human cells, such as the Hippo pathway, which is a key tumor suppressor network. Further investigation into Tem1 and the MEN pathway continues to elucidate mechanisms underlying cell cycle diseases and potential therapeutic targets.

Category:Cell cycle Category:Proteins Category:Yeast proteins