Role of the RAM Network in Cell Polarity and Hyphal Morphogenesis in<i>Candida albicans</i>

Song, Young-Gi; Cheon, Seon Ah; Lee, Jun Young; Lee, So‐Yeon; Lee, Byung-Kyu; Oh, Doo-Byung; Kang, Hyun Ah; Kim, Jeong‐Yoon

doi:10.1091/mbc.e08-03-0272

Cited by 74 publications

(132 citation statements)

References 70 publications

(89 reference statements)

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“…As in budding yeast, the RAM network is required for Ace2 function in C. albicans (44,59), and regulatory sites by which S. cerevisiae Cbk1 controls Ace2 are preserved in the C. albicans Ace2 ortholog (data not shown). While it is not clear if RAM network function is downstream of Cdc14 in C. albicans, the high degree of conservation of the system's components suggest that a similar regulatory organization might exist in this diverged yeast.…”

mentioning

confidence: 93%

Mitotic Exit Control of the Saccharomyces cerevisiae Ndr/LATS Kinase Cbk1 Regulates Daughter Cell Separation after Cytokinesis

Brace

Hsu

Weiss

2011

Molecular and Cellular Biology

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Saccharomyces cerevisiae cell division ends with destruction of a septum deposited during cytokinesis; this must occur only after the structure's construction is complete. Genes involved in septum destruction are induced by the transcription factor Ace2, which is activated by the kinase Cbk1, an Ndr/LATS-related protein that functions in a system related to metazoan hippo pathways. Phosphorylation of a conserved hydrophobic motif (HM) site regulates Cbk1; at peak levels in late mitosis we found that approximately 3% of Cbk1 carries this modification. HM site phosphorylation prior to mitotic exit occurs in response to activation of the FEAR (Cdc fourteen early anaphase release) pathway. However, HM site phosphorylation is not sufficient for Cbk1 to act on Ace2: the kinase is also negatively regulated prior to cytokinesis, likely by cyclin-dependent kinase (CDK) phosphorylation. Cbk1 cannot phosphorylate Ace2 until after mitotic exit network (MEN)-initiated release of the phosphatase Cdc14. Treatment of Cbk1 with Cdc14 in vitro does not increase its intrinsic enzymatic activity, but Cdc14 is required for Cbk1 function in vivo. Thus, we propose that Cdc14 coordinates cell separation with mitotic exit via FEAR-initiated phosphorylation of the Cbk1 HM site and MEN-activated reversal of mitotic CDK phosphorylations that block both Cbk1 and Ace2 function.

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confidence: 93%

Mitotic Exit Control of the Saccharomyces cerevisiae Ndr/LATS Kinase Cbk1 Regulates Daughter Cell Separation after Cytokinesis

Brace

Hsu

Weiss

2011

Molecular and Cellular Biology

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“…For instance, in MOR mutant cells from S. pombe, C. albicans and N. crassa, the actin cytoskeleton appears dispersed around the cell cortex (Hou et al, 2003;Song et al, 2008;Verde et al, 1998;Ziv et al, 2009). In contrast, in C. neoformans it was described that the hyperpolarized growth associated to RAM mutants correlated with abnormal actin localization at the growing tips (Walton et al, 2006).…”

mentioning

confidence: 99%

The distinct wiring between cell cycle regulation and the widely conserved Morphogenesis-Related (MOR) pathway in the fungus Ustilago maydis determines the morphological outcome

Sartorel

Pérez-Martı́n

2012

Journal of Cell Science

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SummaryThe morphogenesis-related NDR kinase (MOR) pathway regulates morphogenesis in fungi. In spite of the high conservation of its components, impairing their functions results in highly divergent cellular responses depending on the fungal species. The reasons for such differences are unclear. Here we propose that the species-specific connections between cell cycle regulation and the MOR pathway could be partly responsible for these divergences. We based our conclusion on the characterization of the MOR pathway in the fungus Ustilago maydis. Each gene that encodes proteins of this pathway in U. maydis was deleted. All mutants exhibited a constitutive hyperpolarized growth, contrasting with the loss of polarity observed in other fungi. Using a conditional allele of the central NDR kinase Ukc1, we found that impairing MOR function resulted in a prolonged G2 phase. This cell cycle delay appears to be the consequence of an increase in Cdk1 inhibitory phosphorylation. Strikingly, prevention of the inhibitory Cdk1 phosphorylation abolished the hyperpolarized growth associated with MOR pathway depletion. We found that the prolonged G2 phase resulted in higher levels of expression of crk1, a conserved kinase that promotes polar growth in U. maydis. Deletion of crk1 also abolished the dramatic activation of polar growth in cells lacking the MOR pathway. Taken together, our results suggest that Cdk1 inhibitory phosphorylation may act as an integrator of signaling cascades regulating fungal morphogenesis and that the distinct morphological response observed in U. maydis upon impairment of the MOR pathway could be due to a cell cycle deregulation.

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“…Kamthan et al (2014) observed that depletion of MPS1 through the use of a methionine-regulated allele led to actively dividing cells with buds lacking nuclei, indicating that MPS1 is required for proper mitosis. Song et al (2008) had also previously shown that mitotic defects were present in cbk1D/D strains. We therefore examined the nuclear segregation of the corresponding single and double heterozygous cbk1 and mps1 strains.…”

Section: Mitotic Defects Of Mps1 Mutants Are Exacerbated By Loss Of Cmentioning

confidence: 71%

“…In S. cerevisiae, Cbk1 plays functions in the mitotic exit network (MEN) and in the regulation of cytokinesis (Weiss 2012). In addition, C. albicans cells lacking components of the RAM pathway show increased levels of multinucleate cells (Song et al 2008). MPS1 expression is increased by hyphae-inducing conditions in a PKA/Efg1-dependent manner (Kamthan et al 2014).…”

Section: Mitotic Defects Of Mps1 Mutants Are Exacerbated By Loss Of Cmentioning

confidence: 99%

“…The previous complex haploinsufficiency screen was performed using Spider medium as the filament-inducing conditions (Bharucha et al 2011) and, in addition to revealing the PKA pathway interaction, identified a large number of Ace2 targets. Ace2 is required for normal filament formation in Spider medium but is dispensable when serum is used (Kelly et al 2004); Cbk1, on the other hand, is required for filament formation under either conditions Song et al 2008). To identify additional, potentially Ace2-independent interactors with Cbk1 during filamentation, we screened our library of transposonmutagenized cbk1D/CBK1 complex heterozygotes for strains with decreased filamentation on serum medium.…”

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confidence: 99%

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Complex Haploinsufficiency-Based Genetic Analysis of the NDR/Lats Kinase Cbk1 Provides Insight into Its Multiple Functions in Candida albicans

et al. 2016

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Although the analysis of genetic interactions and networks is a powerful approach to understanding biology, it has not been applied widely to the pathogenic yeast Candida albicans. Here, we describe the use of both screening and directed genetic interaction studies based on complex haploinsufficiency to probe the function of the Regulation of Ace2 and Morphogenesis (RAM) pathway in C. albicans. A library of 5200 Tn7-mutagenized derivatives of a parental strain heterozygous at CBK1, the key kinase in the RAM pathway, was screened for alterations in serum-induced filamentation. Following confirmation of phenotypes and identification of insertion sites by sequencing, a set of 36 unique double heterozygous strains showing complex haploinsufficiency was obtained. In addition to a large set of genes regulated by the RAM transcription factor Ace2, genes related to cell wall biosynthesis, cell cycle, polarity, oxidative stress, and nitrogen utilization were identified. Follow-up analysis led to the first demonstration that the RAM pathway is required for oxidative stress tolerance in a manner related to the two-component-regulated kinase Chk1 and revealed a potential direct connection between the RAM pathway and the essential Mps1 spindle pole-related kinase. In addition, genetic interactions with CDC42-related genes MSB1, a putative scaffold protein, and RGD3, a putative Rho GTPase-activating protein (GAP) were identified. We also provide evidence that Rgd3 is a GAP for Cdc42 and show that its localization and phosphorylation are dependent on Cbk1.

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Role of the RAM Network in Cell Polarity and Hyphal Morphogenesis inCandida albicans

Cited by 74 publications

References 70 publications

Mitotic Exit Control of the Saccharomyces cerevisiae Ndr/LATS Kinase Cbk1 Regulates Daughter Cell Separation after Cytokinesis

Mitotic Exit Control of the Saccharomyces cerevisiae Ndr/LATS Kinase Cbk1 Regulates Daughter Cell Separation after Cytokinesis

The distinct wiring between cell cycle regulation and the widely conserved Morphogenesis-Related (MOR) pathway in the fungus Ustilago maydis determines the morphological outcome

Complex Haploinsufficiency-Based Genetic Analysis of the NDR/Lats Kinase Cbk1 Provides Insight into Its Multiple Functions in Candida albicans

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