Sugar signals pedal the cell cycle!

Abstract

Cell cycle involves the sequential and reiterative progression of important events leading to cell division. Progression through a specific phase of the cell cycle is under the control of various factors. Since the cell cycle in multicellular eukaryotes responds to multiple extracellular mitogenic cues, its study in higher forms of life becomes all the more important. One such factor regulating cell cycle progression in plants is sugar signalling. Because the growth of organs depends on both cell growth and proliferation, sugars sensing and signalling are key control points linking sugar perception to regulation of downstream factors which facilitate these key developmental transitions. However, the basis of cell cycle control via sugars is intricate and demands exploration. This review deals with the information on sugar and TOR-SnRK1 signalling and how they manoeuvre various events of the cell cycle to ensure proper growth and development.

Keywords: CDK (cyclin-dependent kinase); SnRK1 kinase; glucose; sugar signalling; target of rapamycin (TOR).

Figure 1

TOR regulation of cell cycle in different organisms. (A) In mammals, mTORC1-mediated signalling is relayed through the activation of its downstream effectors S6K1 and 4E-BP1 which regulate cell growth and cell cycle progression. Besides this, mTOR also controls the activation of various cyclins and CDKs which promote progression of different phases of the cell cycle (B) In Saccharomyces cerevesiae, the TORC1 favours progression of the cycle through activation of several G₁ cyclins which activate various CDKs promoting the transition from G₁ to S phase. Additionally Sch9, a major target of TORC1, which apart from controlling translation initiation and ribosome biogenesis also regulates entry into G₀ (quiescence) (C) In plants, TOR, similar to the mammalian and yeast counterpart, controls phosphorylation events crucial for cell expansion and proliferation. This, in part, is mediated through S6K1 phosphorylation which integrates with the cell cycle machinery to favour growth over proliferation (see main text). Unlike S6K1, YAK1 is a negative regulator of growth. Phosphorylation by TOR inhibits YAK1’s activity which relieves the inhibition of CDKs by SMRs. Green arrows indicate direct phosphorylation by upstream targets.

Figure 2

The regulation by AMP/SNF1/SnRK1 pathways of cell growth and proliferation. (A) In mammals, AMPK is essential to maintain genome integrity through phosphorylation of p53, leading to cell cycle arrest upon sensing DNA damage. Parallely, under starvation conditions AMPK overcomes mTORC1 signalling through RAPTOR phosphorylation. Besides this stress-triggered AMPK activation also induces autophagy (B) In Saccharomyces cerevisiae, under glucose limitation the SNF1 protein kinase modulates the expression of several factors crucial for DNA replication, repair and metabolism. Additionally, the Sch9 is inhibited by SNF1 under starvation conditions, thereby attenuating TORC1-mediated energy signalling. (C) In plants, SnRK1 mediates autophagy induction through activation of various ATG proteins. Furthermore, SnRK1 is activated through components of autophagy such as ATG8 by relieving its repression by the FLZ14 protein, which in turn controls the regulation of SnRK1 activity, hence forming a positive feedback loop. In addition, SnRK1 also controls cell growth and divisions through activation of the SOG1 protein under energy stressed conditions. Green arrows indicate direct phosphorylation by upstream targets.

Figure 3

Regulation of the cell cycle components by integration of the sugar-TOR-SnRK1 signalling in the model plant Arabidopsis. Photosynthetically derived sugars drive various stages of the cell cycle. Glucose, the major end product of the light reactions activates TOR signalling which is repressed under starvation conditions by the SnRK1 signalling. Moreover, auxin activation of the ROP2 protein leads to its direct interaction with TOR, resulting in its phosphorylation, which further relays the signals to its downstream effectors like S6K1 and RPS6. The most common readout of TOR activity, the S6K1 protein however, exerts its effect on cell size rather than cell proliferation. S6K1 enhances cell growth and this is related to its RBR1 activating capacity through the promotion of its localization into the nucleus where it inhibits E2Fb protein activity. On the contrary the CYCD3;1-CDKA1 module is necessary for phosphorylation of RBR1, thereby promoting its retention in the cytoplasm. Sugar availability also leads to direct phosphorylation by TOR of the E2Fa/E2Fb proteins (N-terminal) that regulate the expression of various G1 to S phase marker genes encoding proteins required for DNA replication. E2Fa is repressed by hypophosphorylated RBR1 resulting in the inhibition of its transcription-inducing capacity. On the other hand, E2Fa is also directly phosphorylated (T314/T315) by the SnRK1 resulting in its degradation, the result of which is reduced transcription of these genes. Contrarily, SnRK1 also positively impacts cell cycle progression through direct phosphorylation of KRPs which abrogates their binding with cyclin/CDK complexes. Glucose-TOR signalling might also exert control over the G2 to M phase of the cell cycle through its interaction with the YAK1, which is involved in the suppression of various CDKs through activation of the SMRs. Moreover, metabolic sugars also directly control the expression of CYCB1;1/CDKB1 which is required for activation of cell division at the meristems.