Polar opposites: Fine-tuning cytokinesis through SIN asymmetry

Abstract

Mitotic exit and cell division must be spatially and temporally integrated to facilitate equal division of genetic material between daughter cells. In the fission yeast, Schizosaccharomyces pombe, a spindle pole body (SPB) localized signaling cascade termed the septation initiation network (SIN) couples mitotic exit with cytokinesis. The SIN is controlled at many levels to ensure that cytokinesis is executed once per cell cycle and only after cells segregate their DNA. An interesting facet of the SIN is that its activity is asymmetric on the two SPBs during anaphase; however, how and why the SIN is asymmetric has remained elusive. Many key factors controlling SIN asymmetry have now been identified, shedding light on the significance of SIN asymmetry in regulating cytokinesis. In this review, we highlight recent advances in our understanding of SIN regulation, with an emphasis on how SIN asymmetry is achieved and how this aspect of SIN regulation fine-tunes cytokinesis.

Figure 1

A. The essential signaling components of the SIN/MEN pathways in S. pombe, S. cerevisiae and H. sapiens. In S. pombe, the SIN is anchored to SPBs via a bipartite scaffold complex, Cdc11-Sid4. During interphase, the Cdc16-Byr4 GAP complex inhibits the Spg1 GTPase to hold it in its GDP-bound form. Upon mitotic entry, Plo1 promotes Spg1 activation, perhaps through inhibition of Cdc16-Byr4 allowing Spg1 to switch to its active GTP-bound form. Spg1-GTP binds its effector kinase Cdc7 and elicits activation of the downstream SIN kinases Sid1-Cdc14 and Sid2-Mob1. Upon activation, Sid2-Mob1 translocates to the CR and presumably phopshorylates key substrates that promote CR assembly and constriction. Similar mechanisms of SIN/MEN activation also occur in S. cerevisiae and H. sapiens. B. Phenotype observed when the SIN is inactivated. Inactivating mutations in SIN activators cdc11, sid4, spg1, cdc7, sid1, cdc14, sid2, mob1, and etd1 produce multinucleate cells as a result of cytokinesis failure. C. Phenotype observed when the SIN is hyper-active. Inactivating mutations in the SIN inhibitors byr4 and cdc16 produce multi-septated cells.

Figure 2

Organization of SIN components at SPBs during interphase (A). mitosis (B) and a mitotic checkpoint (C). Proteins in contact indicate interactions detected by two-hybrid or in vitro experiments and dashed lines indicate potential interactions based on epistatic experiments.

Figure 3

Localization patterns of the SIN signaling proteins at the ‘old’ and ‘new’ SPBs throughout mitosis. (1) In interphase and early pro-metaphase, Byr4-Cdc16 localize to both SPBs and maintains Spg1 in its GDP-bound inactive state. (2) Then, in late pro-metaphase to metaphase, Cdc7 localizes to both SPBs via interaction with Spg1-GTP. (3) As the spindle begins to elongate in anaphase, Cdc7 disappears from the ‘old’ pole and Byr4-Cdc16 returns to the ‘old’ pole to inactivate the SIN and establish SIN asymmetry. (4) Later in mitosis when CDK activity is low, Sid1-Cdc14 localizes to the ‘new’ SPB with active SIN signaling and as the SPBs reach the cell cortex, Etd1 contacts Spg1 and further activates the SIN on the ‘new’ pole. Since Spg1 is bound to the inhibitory GAP complex (Byr4-Cdc16) on the ‘old’ pole, Etd1 is probably prevented from contacting Spg1 on the ‘old’ pole. Once the spindle is fully elongated, Sid2-Mob1 translocates to the division site and induces CR constriction. (5) After septation, Etd1 disappears from the cell compartment with active SIN signaling and Byr4-Cdc16 returns to this SPB to terminate SIN signaling.

Figure 4

A. Model for potential positive and negative feedback loops that break SIN symmetry during anaphase. Cooperative efforts between Byr4, the Fin1 kinase and PP2A phosphatases inhibit the SIN on the ‘old’ pole, while Sid2, Cdc7, Cdc11 and Etd1 contribute to SIN hyper-activation on the ‘new’ pole. B. Post-translational modifications identified for the core SIN proteins and the validated or potential enzymes that promote or antagonize these modifications.