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PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein.

Todd MA, Ivanochko D, Picketts DJ - Genes (Basel) (2015)

Bottom Line: Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function.In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus.Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada. mtodd.research@gmail.com.

ABSTRACT
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson-Forssman-Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

No MeSH data available.


Related in: MedlinePlus

Model for the putative CDK2- and PLK1-dependent phosphorylation of PHF6. Large-scale proteomic studies identified PHF6 Ser-145, -154, and -155 as phosphorylated residues. The phosphorylation of these sites during mitosis or in response to T-cell receptor signalling likely occurs through a mechanism whereby (A) CDK2 phosphorylates Ser-155, allowing recognition by the Polo-binding domain (PBD) of PLK1 (B), which subsequently phosphorylates Ser-145, which is situated in a PLK1 consensus sequence (143-EESFNE-148), resulting in PHF6 becoming dually phosphorylated at these two sites (C).
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genes-06-00325-f003: Model for the putative CDK2- and PLK1-dependent phosphorylation of PHF6. Large-scale proteomic studies identified PHF6 Ser-145, -154, and -155 as phosphorylated residues. The phosphorylation of these sites during mitosis or in response to T-cell receptor signalling likely occurs through a mechanism whereby (A) CDK2 phosphorylates Ser-155, allowing recognition by the Polo-binding domain (PBD) of PLK1 (B), which subsequently phosphorylates Ser-145, which is situated in a PLK1 consensus sequence (143-EESFNE-148), resulting in PHF6 becoming dually phosphorylated at these two sites (C).

Mentions: Two other studies have identified the phosphorylation of three serine residues (S145; S154; and S155) during mitosis and in response to T-cell receptor signalling [106,107]. Interestingly, S145 phosphorylation is only ever observed in combination with phosphorylation at S155. Other high throughput screens indicate that S145 is a Polo-like kinase 1 (PLK1) target; consistent with its situation in a PLK1 consensus sequence; while phosphorylation at S155 provides a binding site for the polo binding domain of PLK1 (PBD); suggesting a mechanism whereby phosphorylation at S155 primes S145 for PLK1-mediated phosphorylation (see Figure 3) [108,110,111]. Indeed PLK1 inhibition reduces S145 phosphorylation with concomitant accumulation of singularly phosphorylated S155 peptide [108,112]. Interestingly, another screen identified S155 as a candidate substrate for CDK2 phosphorylation, and CDK2 inhibition interferes with the ability of PHF6 to localize to the nucleolus [113,114]. While the exact mechanism of this serine phosphorylation network within PHF6 requires more direct validation; it should be noted that PLK1 and CDK2 are highly active during S and G2 phase when nucleolar size and the rate of ribosome biogenesis is higher relative to G1 [115,116]. Moreover, these phosphorylation sites are directly adjacent to the NoLS. Thus, we speculate that these phosphorylation events may promote shuttling of PHF6 between the nucleoplasm and nucleolus in response to external needs, such as compensation for the increased rates of rRNA synthesis that precede cytokinesis or following T-cell receptor activation during lymphogenesis.


PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein.

Todd MA, Ivanochko D, Picketts DJ - Genes (Basel) (2015)

Model for the putative CDK2- and PLK1-dependent phosphorylation of PHF6. Large-scale proteomic studies identified PHF6 Ser-145, -154, and -155 as phosphorylated residues. The phosphorylation of these sites during mitosis or in response to T-cell receptor signalling likely occurs through a mechanism whereby (A) CDK2 phosphorylates Ser-155, allowing recognition by the Polo-binding domain (PBD) of PLK1 (B), which subsequently phosphorylates Ser-145, which is situated in a PLK1 consensus sequence (143-EESFNE-148), resulting in PHF6 becoming dually phosphorylated at these two sites (C).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488667&req=5

genes-06-00325-f003: Model for the putative CDK2- and PLK1-dependent phosphorylation of PHF6. Large-scale proteomic studies identified PHF6 Ser-145, -154, and -155 as phosphorylated residues. The phosphorylation of these sites during mitosis or in response to T-cell receptor signalling likely occurs through a mechanism whereby (A) CDK2 phosphorylates Ser-155, allowing recognition by the Polo-binding domain (PBD) of PLK1 (B), which subsequently phosphorylates Ser-145, which is situated in a PLK1 consensus sequence (143-EESFNE-148), resulting in PHF6 becoming dually phosphorylated at these two sites (C).
Mentions: Two other studies have identified the phosphorylation of three serine residues (S145; S154; and S155) during mitosis and in response to T-cell receptor signalling [106,107]. Interestingly, S145 phosphorylation is only ever observed in combination with phosphorylation at S155. Other high throughput screens indicate that S145 is a Polo-like kinase 1 (PLK1) target; consistent with its situation in a PLK1 consensus sequence; while phosphorylation at S155 provides a binding site for the polo binding domain of PLK1 (PBD); suggesting a mechanism whereby phosphorylation at S155 primes S145 for PLK1-mediated phosphorylation (see Figure 3) [108,110,111]. Indeed PLK1 inhibition reduces S145 phosphorylation with concomitant accumulation of singularly phosphorylated S155 peptide [108,112]. Interestingly, another screen identified S155 as a candidate substrate for CDK2 phosphorylation, and CDK2 inhibition interferes with the ability of PHF6 to localize to the nucleolus [113,114]. While the exact mechanism of this serine phosphorylation network within PHF6 requires more direct validation; it should be noted that PLK1 and CDK2 are highly active during S and G2 phase when nucleolar size and the rate of ribosome biogenesis is higher relative to G1 [115,116]. Moreover, these phosphorylation sites are directly adjacent to the NoLS. Thus, we speculate that these phosphorylation events may promote shuttling of PHF6 between the nucleoplasm and nucleolus in response to external needs, such as compensation for the increased rates of rRNA synthesis that precede cytokinesis or following T-cell receptor activation during lymphogenesis.

Bottom Line: Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function.In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus.Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada. mtodd.research@gmail.com.

ABSTRACT
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson-Forssman-Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

No MeSH data available.


Related in: MedlinePlus