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Centriole assembly and the role of Mps1: defensible or dispensable?

Pike AN, Fisk HA - Cell Div (2011)

Bottom Line: The Mps1 protein kinase is an intriguing and controversial player in centriole assembly.Recent studies of Mps1 have identified at least two distinct functions for Mps1 in centriole assembly, while simultaneously supporting the notion that Mps1 is dispensable for the process.However, the fact that at least one centrosomal substrate of Mps1 is conserved from yeast to humans down to the phosphorylation site, combined with evidence demonstrating the exquisite control exerted over centrosomal Mps1 levels suggest that the notion of being essential may not be the most important of distinctions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Genetics, The Ohio State University, 484 W, 12th Avenue, Columbus OH 43210-1292, USA. fisk.13@osu.edu.

ABSTRACT
The Mps1 protein kinase is an intriguing and controversial player in centriole assembly. Originally shown to control duplication of the budding yeast spindle pole body, Mps1 is present in eukaryotes from yeast to humans, the nematode C. elegans being a notable exception, and has also been shown to regulate the spindle checkpoint and an increasing number of cellular functions relating to genomic stability. While its function in the spindle checkpoint appears to be both universally conserved and essential in most organisms, conservation of its originally described function in spindle pole duplication has proven controversial, and it is less clear whether Mps1 is essential for centrosome duplication outside of budding yeast. Recent studies of Mps1 have identified at least two distinct functions for Mps1 in centriole assembly, while simultaneously supporting the notion that Mps1 is dispensable for the process. However, the fact that at least one centrosomal substrate of Mps1 is conserved from yeast to humans down to the phosphorylation site, combined with evidence demonstrating the exquisite control exerted over centrosomal Mps1 levels suggest that the notion of being essential may not be the most important of distinctions.

No MeSH data available.


Related in: MedlinePlus

Modes of centriole over production. We propose that hMps1 and Cetn2 cooperate to generate centriole overproduction by two distinct mechanisms. First, in Mps1Δ12/13-induced centriole overproduction, hMps1Δ12/13 promotes the assembly of multiple hSas6 containing precursors (analogous to the proposed hSas6-containing intermediate in procentriole assembly described in Figure 3). As in the canonical centriole assembly pathway, we assume that hMps1 is required for the remodeling of these precursors into cartwheels, onto which procentrioles are assembled. The figure reflects the possibility that not all of the precursors become cartwheels, based on the observation that the percentage of cells with excess hSas6 foci is greater than the percentage of cells with excess γ-Tubulin or CP110 foci [28]. Second, hMps1 is also required for initiation of Cetn2-induced centriole overproduction. We propose that overexpression of wild type Cetn2 leads to the assembly of Cetn2-containing precursors that organize distal centriole modules in a top-down fashion that is independent of hSas6. Because Mps1 is required for the initiation of these structures, we cannot assess a role for Mps1 in their maturation. However, while the initiation of these structures is hSas6-independent, some aspects of their maturation require hSas6, as suggested by the observation that a subset of centriole proteins are not recruited to these structures in the absence of hSas6 [28]. Because these structures recruit hSas6, it is possible that they can recruit cartwheels (indicated by a question mark). Structures and colors are as in Figure 3.
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Figure 4: Modes of centriole over production. We propose that hMps1 and Cetn2 cooperate to generate centriole overproduction by two distinct mechanisms. First, in Mps1Δ12/13-induced centriole overproduction, hMps1Δ12/13 promotes the assembly of multiple hSas6 containing precursors (analogous to the proposed hSas6-containing intermediate in procentriole assembly described in Figure 3). As in the canonical centriole assembly pathway, we assume that hMps1 is required for the remodeling of these precursors into cartwheels, onto which procentrioles are assembled. The figure reflects the possibility that not all of the precursors become cartwheels, based on the observation that the percentage of cells with excess hSas6 foci is greater than the percentage of cells with excess γ-Tubulin or CP110 foci [28]. Second, hMps1 is also required for initiation of Cetn2-induced centriole overproduction. We propose that overexpression of wild type Cetn2 leads to the assembly of Cetn2-containing precursors that organize distal centriole modules in a top-down fashion that is independent of hSas6. Because Mps1 is required for the initiation of these structures, we cannot assess a role for Mps1 in their maturation. However, while the initiation of these structures is hSas6-independent, some aspects of their maturation require hSas6, as suggested by the observation that a subset of centriole proteins are not recruited to these structures in the absence of hSas6 [28]. Because these structures recruit hSas6, it is possible that they can recruit cartwheels (indicated by a question mark). Structures and colors are as in Figure 3.

Mentions: Interestingly, our study of Cetn2 also suggests that Cetn2 has multiple roles in centriole assembly. Mutations that mimic phosphorylation at any of the three hMps1 phosphorylation sites, e.g. Cetn2T118D, led to a robust overproduction of bona fide centrioles [28]. The ability of phosphomimetic Cetn2 mutants to promote centriole overproduction required hSas6 [28], suggesting that hMps1 phosphorylation sites within Cetn2 stimulate centriole overproduction through cartwheel templates. Centriole overproduction in cells expressing phosphomimetic Cetn2 mutants also required hMps1 [28], further supporting the suggestion that additional centriolar hMps1 substrates must exist. Interestingly, we found that overexpression of wild type Cetn2 led to the overproduction of both bona fide centrioles and aberrant centriole-like structures [28] that required hMps1 but not hSas6, suggesting that wild type Cetn2 did not lead to centriole overproduction through a cartwheel template. These observations suggest that Mps1 and Cetn2 cooperate to promote centriole overproduction via multiple mechanisms (Figure 4). First, expression of the non-degradable hMps1Δ12/13 induces the typical "Bottom-up" production of excess centrioles via hSas6-containing precursors. The initiation step does not require Cetn2, but is followed by the Cetn2-dependent maturation of these structures into centrioles. Although it remains to be tested, this pathway is presumably similar to that induced by overexpression of Plk4 or hSas6. Second, hMps1 is also required for the production of excess centriole-like structures induced by overexpression of wild type Cetn2. Because it does not require hSas6, the assembly of these structures is presumably initiated from Cetn2-containing precursors that first organize distal centriole elements, and then recruit proximal elements such as Cep135 and hSas6 in a "Top-down" fashion. Because these Cetn2-induced structures can recruit hSas6, it seems possible that they may contain cartwheels, although their initiation is not cartwheel dependent. While the initiation step in Cetn2-induced centriole overproduction does not require hSas6, some aspects of the maturation of these structures is hSas6-dependent; in the absence of hSas6 these structures can no longer recruit proximal centriole elements like Cep135, although they can still recruit pericentriolar material and function as mitotic spindle poles [28]. Together, these studies on OAZ and Cetn2 support the suggestion that hMps1 has both an early role in procentriole assembly, and a later Cetn2-dependent role in centriole maturation. Consistent with findings from yeast [76-78], our studies suggest that hMps1 phosphorylation of centriolar protein(s) remodels protein complexes to promote initiation and maturation of procentrioles, and that this is relevant to both the canonical centriole assembly pathway and centriole overproduction.


Centriole assembly and the role of Mps1: defensible or dispensable?

Pike AN, Fisk HA - Cell Div (2011)

Modes of centriole over production. We propose that hMps1 and Cetn2 cooperate to generate centriole overproduction by two distinct mechanisms. First, in Mps1Δ12/13-induced centriole overproduction, hMps1Δ12/13 promotes the assembly of multiple hSas6 containing precursors (analogous to the proposed hSas6-containing intermediate in procentriole assembly described in Figure 3). As in the canonical centriole assembly pathway, we assume that hMps1 is required for the remodeling of these precursors into cartwheels, onto which procentrioles are assembled. The figure reflects the possibility that not all of the precursors become cartwheels, based on the observation that the percentage of cells with excess hSas6 foci is greater than the percentage of cells with excess γ-Tubulin or CP110 foci [28]. Second, hMps1 is also required for initiation of Cetn2-induced centriole overproduction. We propose that overexpression of wild type Cetn2 leads to the assembly of Cetn2-containing precursors that organize distal centriole modules in a top-down fashion that is independent of hSas6. Because Mps1 is required for the initiation of these structures, we cannot assess a role for Mps1 in their maturation. However, while the initiation of these structures is hSas6-independent, some aspects of their maturation require hSas6, as suggested by the observation that a subset of centriole proteins are not recruited to these structures in the absence of hSas6 [28]. Because these structures recruit hSas6, it is possible that they can recruit cartwheels (indicated by a question mark). Structures and colors are as in Figure 3.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3094359&req=5

Figure 4: Modes of centriole over production. We propose that hMps1 and Cetn2 cooperate to generate centriole overproduction by two distinct mechanisms. First, in Mps1Δ12/13-induced centriole overproduction, hMps1Δ12/13 promotes the assembly of multiple hSas6 containing precursors (analogous to the proposed hSas6-containing intermediate in procentriole assembly described in Figure 3). As in the canonical centriole assembly pathway, we assume that hMps1 is required for the remodeling of these precursors into cartwheels, onto which procentrioles are assembled. The figure reflects the possibility that not all of the precursors become cartwheels, based on the observation that the percentage of cells with excess hSas6 foci is greater than the percentage of cells with excess γ-Tubulin or CP110 foci [28]. Second, hMps1 is also required for initiation of Cetn2-induced centriole overproduction. We propose that overexpression of wild type Cetn2 leads to the assembly of Cetn2-containing precursors that organize distal centriole modules in a top-down fashion that is independent of hSas6. Because Mps1 is required for the initiation of these structures, we cannot assess a role for Mps1 in their maturation. However, while the initiation of these structures is hSas6-independent, some aspects of their maturation require hSas6, as suggested by the observation that a subset of centriole proteins are not recruited to these structures in the absence of hSas6 [28]. Because these structures recruit hSas6, it is possible that they can recruit cartwheels (indicated by a question mark). Structures and colors are as in Figure 3.
Mentions: Interestingly, our study of Cetn2 also suggests that Cetn2 has multiple roles in centriole assembly. Mutations that mimic phosphorylation at any of the three hMps1 phosphorylation sites, e.g. Cetn2T118D, led to a robust overproduction of bona fide centrioles [28]. The ability of phosphomimetic Cetn2 mutants to promote centriole overproduction required hSas6 [28], suggesting that hMps1 phosphorylation sites within Cetn2 stimulate centriole overproduction through cartwheel templates. Centriole overproduction in cells expressing phosphomimetic Cetn2 mutants also required hMps1 [28], further supporting the suggestion that additional centriolar hMps1 substrates must exist. Interestingly, we found that overexpression of wild type Cetn2 led to the overproduction of both bona fide centrioles and aberrant centriole-like structures [28] that required hMps1 but not hSas6, suggesting that wild type Cetn2 did not lead to centriole overproduction through a cartwheel template. These observations suggest that Mps1 and Cetn2 cooperate to promote centriole overproduction via multiple mechanisms (Figure 4). First, expression of the non-degradable hMps1Δ12/13 induces the typical "Bottom-up" production of excess centrioles via hSas6-containing precursors. The initiation step does not require Cetn2, but is followed by the Cetn2-dependent maturation of these structures into centrioles. Although it remains to be tested, this pathway is presumably similar to that induced by overexpression of Plk4 or hSas6. Second, hMps1 is also required for the production of excess centriole-like structures induced by overexpression of wild type Cetn2. Because it does not require hSas6, the assembly of these structures is presumably initiated from Cetn2-containing precursors that first organize distal centriole elements, and then recruit proximal elements such as Cep135 and hSas6 in a "Top-down" fashion. Because these Cetn2-induced structures can recruit hSas6, it seems possible that they may contain cartwheels, although their initiation is not cartwheel dependent. While the initiation step in Cetn2-induced centriole overproduction does not require hSas6, some aspects of the maturation of these structures is hSas6-dependent; in the absence of hSas6 these structures can no longer recruit proximal centriole elements like Cep135, although they can still recruit pericentriolar material and function as mitotic spindle poles [28]. Together, these studies on OAZ and Cetn2 support the suggestion that hMps1 has both an early role in procentriole assembly, and a later Cetn2-dependent role in centriole maturation. Consistent with findings from yeast [76-78], our studies suggest that hMps1 phosphorylation of centriolar protein(s) remodels protein complexes to promote initiation and maturation of procentrioles, and that this is relevant to both the canonical centriole assembly pathway and centriole overproduction.

Bottom Line: The Mps1 protein kinase is an intriguing and controversial player in centriole assembly.Recent studies of Mps1 have identified at least two distinct functions for Mps1 in centriole assembly, while simultaneously supporting the notion that Mps1 is dispensable for the process.However, the fact that at least one centrosomal substrate of Mps1 is conserved from yeast to humans down to the phosphorylation site, combined with evidence demonstrating the exquisite control exerted over centrosomal Mps1 levels suggest that the notion of being essential may not be the most important of distinctions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Genetics, The Ohio State University, 484 W, 12th Avenue, Columbus OH 43210-1292, USA. fisk.13@osu.edu.

ABSTRACT
The Mps1 protein kinase is an intriguing and controversial player in centriole assembly. Originally shown to control duplication of the budding yeast spindle pole body, Mps1 is present in eukaryotes from yeast to humans, the nematode C. elegans being a notable exception, and has also been shown to regulate the spindle checkpoint and an increasing number of cellular functions relating to genomic stability. While its function in the spindle checkpoint appears to be both universally conserved and essential in most organisms, conservation of its originally described function in spindle pole duplication has proven controversial, and it is less clear whether Mps1 is essential for centrosome duplication outside of budding yeast. Recent studies of Mps1 have identified at least two distinct functions for Mps1 in centriole assembly, while simultaneously supporting the notion that Mps1 is dispensable for the process. However, the fact that at least one centrosomal substrate of Mps1 is conserved from yeast to humans down to the phosphorylation site, combined with evidence demonstrating the exquisite control exerted over centrosomal Mps1 levels suggest that the notion of being essential may not be the most important of distinctions.

No MeSH data available.


Related in: MedlinePlus