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Animal HECT ubiquitin ligases: evolution and functional implications.

Marín I - BMC Evol. Biol. (2010)

Bottom Line: Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-beta and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles.The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered.The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), Valencia, Spain. imarin@ibv.csic.es

ABSTRACT

Background: HECT ubiquitin ligases (HECT E3s) are key components of the eukaryotic ubiquitin-proteasome system and are involved in the genesis of several human diseases. In this study, I analyze the patterns of diversification of HECT E3s since animals emerged in order to provide the right framework to understand the functional data available for proteins of this family.

Results: I show that the current classification of HECT E3s into three groups (NEDD4-like E3s, HERCs and single-HECT E3s) is fundamentally incorrect. First, the existence of a "Single-HECT E3s" group is not supported by phylogenetic analyses. Second, the HERC proteins must be divided into two subfamilies (Large HERCs, Small HERCs) that are evolutionarily very distant, their structural similarity being due to convergence and not to a common origin. Sequence and structural analyses show that animal HECT E3s can be naturally classified into 16 subfamilies. Almost all of them appeared either before animals originated or in early animal evolution. More recently, multiple gene losses have occurred independently in some lineages (nematodes, insects, urochordates), the same groups that have also lost genes of another type of E3s (RBR family). Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-beta and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles. This may contribute to explain why distantly related HECT E3s are involved in the genesis of multiple types of cancer.

Conclusions: The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered. The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.

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Known substrates of HECT E3s that are related to the TGF-β signaling pathway. Lines connect the enzymes and their corresponding substrates. The presence (+) or absence (-) of genes encoding those substrates in the choanoflagellate Monosiga brevicollis (M. b.) and the placozoan Trichoplax adhaerens (T. a.) is also indicated. NEDD4a - NEDD4d refer to the four genes already present in early animals. A question mark indicates that one or more related genes are detected, but it is unclear whether they are true orthologs of the corresponding human genes. It is clear from this data that NEDD4 genes of different origin ubiquitinate now the same substrates.
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Figure 4: Known substrates of HECT E3s that are related to the TGF-β signaling pathway. Lines connect the enzymes and their corresponding substrates. The presence (+) or absence (-) of genes encoding those substrates in the choanoflagellate Monosiga brevicollis (M. b.) and the placozoan Trichoplax adhaerens (T. a.) is also indicated. NEDD4a - NEDD4d refer to the four genes already present in early animals. A question mark indicates that one or more related genes are detected, but it is unclear whether they are true orthologs of the corresponding human genes. It is clear from this data that NEDD4 genes of different origin ubiquitinate now the same substrates.

Mentions: Elucidating the evolution of the HECT family of E3s may allow for a more precise understanding of how the current functions of these proteins emerged. Although the functional information for animal HECT E3s is largely restricted to mammalian proteins, it is still possible to obtain some ideas of how several functions originated by comparing the patterns of presence/absence of genes encoding HECT proteins and genes encoding their substrates. More precisely, the question that can be tackled is when HECT E3s started to ubiquitinate the substrates that we observe today. Of particular interest are three basic systems present in all animals that are known to be regulated by HECT E3s. The first of them is the transforming growth factor β (TGF-β) signaling pathway, one of the main signal transduction systems in animals, involved in multiple cellular and developmental processes [21]. The TGF-β pathway is precisely regulated by ubiquitination [22,23]. Particularly, it is well established that several members of the NEDD4 subfamily of HECT E3s control, directly or indirectly, TGF-β signaling [4,22,23]. Figure 4 summarizes the known substrates of NEDD4 E3s that are known to be related to the TGF-β signaling pathway. They include from one of the units of the TGF-β receptor (Tβr1) and multiple critical mediators of the pathway (e. g. several Smads) to downstream targets of this signaling system, such as transcription factors that are regulated by TGF-β signaling (e. g. RUNX2, RUNX3) or the protein phosphatase PTEN, a well-known tumor suppressor (see further details in the legend of Figure 4). Figure 4 also includes whether these TGF-β-related proteins are detected in choanoflagellates (Monosiga) or in placozoans (Trichoplax). This allows comparing the origin of the NEDD4 subfamily genes with the origin of their substrates. The picture that emerges is very complex. On one hand, and as it could be expected, some proteins that appeared recently, from vertebrate-specific duplications, have often the same substrates (e. g. the proteins encoded by Smurf1 and Smurf2, originated from a duplication of the ancestral NEDD4c gene; Figures 3, 4). However, on the other hand, and surprisingly, proteins encoded by genes that emerged from duplications that occurred before animals originated also often share substrates. For example, the proteins encoded by NEDD4L, WWP1 and the Smurf genes, which respectively derive from the NEDD4a, NEDD4b and NEDD4c ancestral genes, have multiple common substrates (Figure 4). This similarity is even more surprising, considering that the four ancestral NEDD4 genes (NEDD4a - NEDD4d) originated before the emergence of the TGFβ signaling pathway, which is absent in choanoflagellates ([11]; see also Figure 4). Therefore, it can be deduced that several HECT E3s have - independently and long after they arose -- acquired the ability to modify the same substrates.


Animal HECT ubiquitin ligases: evolution and functional implications.

Marín I - BMC Evol. Biol. (2010)

Known substrates of HECT E3s that are related to the TGF-β signaling pathway. Lines connect the enzymes and their corresponding substrates. The presence (+) or absence (-) of genes encoding those substrates in the choanoflagellate Monosiga brevicollis (M. b.) and the placozoan Trichoplax adhaerens (T. a.) is also indicated. NEDD4a - NEDD4d refer to the four genes already present in early animals. A question mark indicates that one or more related genes are detected, but it is unclear whether they are true orthologs of the corresponding human genes. It is clear from this data that NEDD4 genes of different origin ubiquitinate now the same substrates.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837046&req=5

Figure 4: Known substrates of HECT E3s that are related to the TGF-β signaling pathway. Lines connect the enzymes and their corresponding substrates. The presence (+) or absence (-) of genes encoding those substrates in the choanoflagellate Monosiga brevicollis (M. b.) and the placozoan Trichoplax adhaerens (T. a.) is also indicated. NEDD4a - NEDD4d refer to the four genes already present in early animals. A question mark indicates that one or more related genes are detected, but it is unclear whether they are true orthologs of the corresponding human genes. It is clear from this data that NEDD4 genes of different origin ubiquitinate now the same substrates.
Mentions: Elucidating the evolution of the HECT family of E3s may allow for a more precise understanding of how the current functions of these proteins emerged. Although the functional information for animal HECT E3s is largely restricted to mammalian proteins, it is still possible to obtain some ideas of how several functions originated by comparing the patterns of presence/absence of genes encoding HECT proteins and genes encoding their substrates. More precisely, the question that can be tackled is when HECT E3s started to ubiquitinate the substrates that we observe today. Of particular interest are three basic systems present in all animals that are known to be regulated by HECT E3s. The first of them is the transforming growth factor β (TGF-β) signaling pathway, one of the main signal transduction systems in animals, involved in multiple cellular and developmental processes [21]. The TGF-β pathway is precisely regulated by ubiquitination [22,23]. Particularly, it is well established that several members of the NEDD4 subfamily of HECT E3s control, directly or indirectly, TGF-β signaling [4,22,23]. Figure 4 summarizes the known substrates of NEDD4 E3s that are known to be related to the TGF-β signaling pathway. They include from one of the units of the TGF-β receptor (Tβr1) and multiple critical mediators of the pathway (e. g. several Smads) to downstream targets of this signaling system, such as transcription factors that are regulated by TGF-β signaling (e. g. RUNX2, RUNX3) or the protein phosphatase PTEN, a well-known tumor suppressor (see further details in the legend of Figure 4). Figure 4 also includes whether these TGF-β-related proteins are detected in choanoflagellates (Monosiga) or in placozoans (Trichoplax). This allows comparing the origin of the NEDD4 subfamily genes with the origin of their substrates. The picture that emerges is very complex. On one hand, and as it could be expected, some proteins that appeared recently, from vertebrate-specific duplications, have often the same substrates (e. g. the proteins encoded by Smurf1 and Smurf2, originated from a duplication of the ancestral NEDD4c gene; Figures 3, 4). However, on the other hand, and surprisingly, proteins encoded by genes that emerged from duplications that occurred before animals originated also often share substrates. For example, the proteins encoded by NEDD4L, WWP1 and the Smurf genes, which respectively derive from the NEDD4a, NEDD4b and NEDD4c ancestral genes, have multiple common substrates (Figure 4). This similarity is even more surprising, considering that the four ancestral NEDD4 genes (NEDD4a - NEDD4d) originated before the emergence of the TGFβ signaling pathway, which is absent in choanoflagellates ([11]; see also Figure 4). Therefore, it can be deduced that several HECT E3s have - independently and long after they arose -- acquired the ability to modify the same substrates.

Bottom Line: Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-beta and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles.The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered.The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), Valencia, Spain. imarin@ibv.csic.es

ABSTRACT

Background: HECT ubiquitin ligases (HECT E3s) are key components of the eukaryotic ubiquitin-proteasome system and are involved in the genesis of several human diseases. In this study, I analyze the patterns of diversification of HECT E3s since animals emerged in order to provide the right framework to understand the functional data available for proteins of this family.

Results: I show that the current classification of HECT E3s into three groups (NEDD4-like E3s, HERCs and single-HECT E3s) is fundamentally incorrect. First, the existence of a "Single-HECT E3s" group is not supported by phylogenetic analyses. Second, the HERC proteins must be divided into two subfamilies (Large HERCs, Small HERCs) that are evolutionarily very distant, their structural similarity being due to convergence and not to a common origin. Sequence and structural analyses show that animal HECT E3s can be naturally classified into 16 subfamilies. Almost all of them appeared either before animals originated or in early animal evolution. More recently, multiple gene losses have occurred independently in some lineages (nematodes, insects, urochordates), the same groups that have also lost genes of another type of E3s (RBR family). Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-beta and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles. This may contribute to explain why distantly related HECT E3s are involved in the genesis of multiple types of cancer.

Conclusions: The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered. The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.

Show MeSH
Related in: MedlinePlus