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Function, regulation and pathological roles of the Gab/DOS docking proteins.

Wöhrle FU, Daly RJ, Brummer T - Cell Commun. Signal (2009)

Bottom Line: Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions.Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease.In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/DOS family.We also summarize recent findings implicating Gab proteins, in particular the Gab2 isoform, in leukaemia, solid tumours and other human diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University of Freiburg, Germany. tilman.brummer@zbsa.de.

ABSTRACT
Since their discovery a little more than a decade ago, the docking proteins of the Gab/DOS family have emerged as important signalling elements in metazoans. Gab/DOS proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine and antigen receptors as well as cell adhesion molecules. They also contribute to signal diversification by channelling the information from activated receptors into signalling pathways with distinct biological functions. Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions. Thus, Gab/DOS docking proteins are at the centre of entire signalling subsystems and fulfil an important if not essential role in many physiological processes. Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease.In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/DOS family. We also summarize recent findings implicating Gab proteins, in particular the Gab2 isoform, in leukaemia, solid tumours and other human diseases.

No MeSH data available.


Related in: MedlinePlus

(A) Simplified phylogenetic tree illustrating the emergence of PTK signaling systems and the emergence of Gab/Dos proteins. The tree is based on recent insights into metazoan evolution and highlights the position of the model organisms in which bona fide Gab/Dos proteins have been identified [137,139,140,240,241]. The distances between the individual clades do not represent phylogenetic or temporal distances. (B) Overall sequence similarity and sequence identity across the PH domains of the various Gab/DOS proteins discussed in this review.
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Figure 4: (A) Simplified phylogenetic tree illustrating the emergence of PTK signaling systems and the emergence of Gab/Dos proteins. The tree is based on recent insights into metazoan evolution and highlights the position of the model organisms in which bona fide Gab/Dos proteins have been identified [137,139,140,240,241]. The distances between the individual clades do not represent phylogenetic or temporal distances. (B) Overall sequence similarity and sequence identity across the PH domains of the various Gab/DOS proteins discussed in this review.

Mentions: Recent genome analyses have revealed that the emergence of PTK signalling networks precedes the advent of true multi-cellularity and that these expand dramatically at the base of the animal kingdom (Fig. 4A; [137-140]). Consequently, these analyses should aid in the identification of the time point of the emergence of Gab, DOS and SOC proteins and would assist in the design and interpretation of structure-function analyses of Gab proteins. We reasoned that if the hallmarks of a Gab protein were the presence of an N-terminal PH domain followed by Pro-rich sequences enabling the recruitment of SH3 domains and the presence of multiple tyrosine phosphorylation motifs for the recruitment of SH2 domains, then it would be possible to search for Gab proteins in lower metazoans and to identify proteins that resemble the last common ancestor of the DOS, SOC and Gab proteins. To this end, we made use of the recently published genomes of the choanoflagellate Monosiga brevicollis, which represents an outgroup to metazoans, and the basal metazoan Trichoplax adhaerens and the starlet sea anemone Nematostella vectensis. Whilst there is no evidence for bona fide Gab/DOS proteins in either the Monosiga nor Trichoplax genomes (our own observations), we and the Feller group identified a Gab-like protein in the Nematostella genome (GenBank entry XP_001636529; [42]). This conceptual protein (NeGab; Fig. 1) carries an N-terminal PH domain of the Gab type (PH_GAB) followed by potential recruitment sites for SH3 domains, of which two and three align almost perfectly with the typical and atypical Grb2 binding domains of human Gab proteins, respectively. These motifs also contain the key residues for the interaction with the C-terminal SH3 domain of Grb2 [42]. It should be noted that the typical Grb2 binding site does not occur in the various DOS proteins and SOC-1 [20]. Importantly, our Scansite analysis revealed that NeGab also carries several tyrosine residues that match phosphorylation motifs involved in the recruitment of SH2-containing proteins such as the Gab signalosome components p85, CrkL and PLCγ (Fig. 1). Overall, these findings are consistent with the presence of orthologues of the Gab signalosome components Grb2, Shc, PLCγ and Crk in Nematostella [137] and database entries for SHP2- and p85-like proteins for another Cnidarian, Hydra magnipapillata (our unpublished observations). However, it should be noted that, whilst there are also tyrosine residues in NeGab that align with those involved in the recruitment of SHP2 to mammalian Gab proteins, the surrounding residues are not conserved and therefore do not constitute a bona fide recognition motif for both SH2 domains of mammalian SHP2 [141]). These findings suggest that either NeGab does not recruit the corresponding SHP2 orthologue or that the NeGab/SHP2 interaction takes place by other means. Nevertheless, according to a Scansite prediction [121], the SH2 binding motifs in NeGab align with one of the CrkL (Y266 in human Gab2) and p85 (Y584) recruitment sites in mammalian Gab proteins. Taken together, these data suggest that at least the Gab/Crk, Gab/PLCγ and Gab/PI3K connections were already established in the precambrium and that a Gab-like docking protein was an early feature of the metazoan PTK signalling toolkit (Fig. 4A).


Function, regulation and pathological roles of the Gab/DOS docking proteins.

Wöhrle FU, Daly RJ, Brummer T - Cell Commun. Signal (2009)

(A) Simplified phylogenetic tree illustrating the emergence of PTK signaling systems and the emergence of Gab/Dos proteins. The tree is based on recent insights into metazoan evolution and highlights the position of the model organisms in which bona fide Gab/Dos proteins have been identified [137,139,140,240,241]. The distances between the individual clades do not represent phylogenetic or temporal distances. (B) Overall sequence similarity and sequence identity across the PH domains of the various Gab/DOS proteins discussed in this review.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2747914&req=5

Figure 4: (A) Simplified phylogenetic tree illustrating the emergence of PTK signaling systems and the emergence of Gab/Dos proteins. The tree is based on recent insights into metazoan evolution and highlights the position of the model organisms in which bona fide Gab/Dos proteins have been identified [137,139,140,240,241]. The distances between the individual clades do not represent phylogenetic or temporal distances. (B) Overall sequence similarity and sequence identity across the PH domains of the various Gab/DOS proteins discussed in this review.
Mentions: Recent genome analyses have revealed that the emergence of PTK signalling networks precedes the advent of true multi-cellularity and that these expand dramatically at the base of the animal kingdom (Fig. 4A; [137-140]). Consequently, these analyses should aid in the identification of the time point of the emergence of Gab, DOS and SOC proteins and would assist in the design and interpretation of structure-function analyses of Gab proteins. We reasoned that if the hallmarks of a Gab protein were the presence of an N-terminal PH domain followed by Pro-rich sequences enabling the recruitment of SH3 domains and the presence of multiple tyrosine phosphorylation motifs for the recruitment of SH2 domains, then it would be possible to search for Gab proteins in lower metazoans and to identify proteins that resemble the last common ancestor of the DOS, SOC and Gab proteins. To this end, we made use of the recently published genomes of the choanoflagellate Monosiga brevicollis, which represents an outgroup to metazoans, and the basal metazoan Trichoplax adhaerens and the starlet sea anemone Nematostella vectensis. Whilst there is no evidence for bona fide Gab/DOS proteins in either the Monosiga nor Trichoplax genomes (our own observations), we and the Feller group identified a Gab-like protein in the Nematostella genome (GenBank entry XP_001636529; [42]). This conceptual protein (NeGab; Fig. 1) carries an N-terminal PH domain of the Gab type (PH_GAB) followed by potential recruitment sites for SH3 domains, of which two and three align almost perfectly with the typical and atypical Grb2 binding domains of human Gab proteins, respectively. These motifs also contain the key residues for the interaction with the C-terminal SH3 domain of Grb2 [42]. It should be noted that the typical Grb2 binding site does not occur in the various DOS proteins and SOC-1 [20]. Importantly, our Scansite analysis revealed that NeGab also carries several tyrosine residues that match phosphorylation motifs involved in the recruitment of SH2-containing proteins such as the Gab signalosome components p85, CrkL and PLCγ (Fig. 1). Overall, these findings are consistent with the presence of orthologues of the Gab signalosome components Grb2, Shc, PLCγ and Crk in Nematostella [137] and database entries for SHP2- and p85-like proteins for another Cnidarian, Hydra magnipapillata (our unpublished observations). However, it should be noted that, whilst there are also tyrosine residues in NeGab that align with those involved in the recruitment of SHP2 to mammalian Gab proteins, the surrounding residues are not conserved and therefore do not constitute a bona fide recognition motif for both SH2 domains of mammalian SHP2 [141]). These findings suggest that either NeGab does not recruit the corresponding SHP2 orthologue or that the NeGab/SHP2 interaction takes place by other means. Nevertheless, according to a Scansite prediction [121], the SH2 binding motifs in NeGab align with one of the CrkL (Y266 in human Gab2) and p85 (Y584) recruitment sites in mammalian Gab proteins. Taken together, these data suggest that at least the Gab/Crk, Gab/PLCγ and Gab/PI3K connections were already established in the precambrium and that a Gab-like docking protein was an early feature of the metazoan PTK signalling toolkit (Fig. 4A).

Bottom Line: Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions.Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease.In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/DOS family.We also summarize recent findings implicating Gab proteins, in particular the Gab2 isoform, in leukaemia, solid tumours and other human diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University of Freiburg, Germany. tilman.brummer@zbsa.de.

ABSTRACT
Since their discovery a little more than a decade ago, the docking proteins of the Gab/DOS family have emerged as important signalling elements in metazoans. Gab/DOS proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine and antigen receptors as well as cell adhesion molecules. They also contribute to signal diversification by channelling the information from activated receptors into signalling pathways with distinct biological functions. Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions. Thus, Gab/DOS docking proteins are at the centre of entire signalling subsystems and fulfil an important if not essential role in many physiological processes. Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease.In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/DOS family. We also summarize recent findings implicating Gab proteins, in particular the Gab2 isoform, in leukaemia, solid tumours and other human diseases.

No MeSH data available.


Related in: MedlinePlus