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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

Potential functional effects of Gab phosphorylation. (A/B) Phosphorylation of one residue affects the phosphorylation of a nearby residue in either a positive or antagonistic fashion. (C) Phosphorylation-induced conformational changes by the cis/trans peptidyl-prolyl-isomerase PIN-1. (D) Phosphorylation affects the composition of multi-protein complexes, e.g. by phosphorylation-induced conformational changes or the creation of docking sites, e.g. for proteins with SH2, PTB, or WW domains or for 14-3-3 proteins. IP A and IP B stand for interaction partners A and B, respectively. For details refer to text.
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Figure 6: Potential functional effects of Gab phosphorylation. (A/B) Phosphorylation of one residue affects the phosphorylation of a nearby residue in either a positive or antagonistic fashion. (C) Phosphorylation-induced conformational changes by the cis/trans peptidyl-prolyl-isomerase PIN-1. (D) Phosphorylation affects the composition of multi-protein complexes, e.g. by phosphorylation-induced conformational changes or the creation of docking sites, e.g. for proteins with SH2, PTB, or WW domains or for 14-3-3 proteins. IP A and IP B stand for interaction partners A and B, respectively. For details refer to text.

Mentions: Potential mechanisms that may underpin the action of phosphorylation-dependent positive or negative feedback on Gab proteins are summarized in Fig. 6. Firstly, phosphorylation of a particular residue might affect the phosphorylation of a nearby residue in either a positive or antagonistic fashion, due to phosphorylation-induced changes in protein conformation or simply changes in the electrostatic landscape of the substrate protein [182] (Fig. 6A/B). Secondly, phosphorylation-induced conformational changes may alter the accessibility of key regions, such as the PH domain. These may occur due to electrostatic repulsion/attraction between distinct protein moieties or phosphorylation-induced cis/trans peptidyl-prolyl-isomerisation (Fig. 6C). Although Gab proteins have not been identified as substrates of peptidyl-prolyl-isomerases such as PIN1 yet [183], the high number of phosphorylation sites preceding proline residues and the fact that Gab proteins are targeted by Pro-directed kinases such as ERK support the likelihood of this regulatory mechanism [80,173,175].


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

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

Potential functional effects of Gab phosphorylation. (A/B) Phosphorylation of one residue affects the phosphorylation of a nearby residue in either a positive or antagonistic fashion. (C) Phosphorylation-induced conformational changes by the cis/trans peptidyl-prolyl-isomerase PIN-1. (D) Phosphorylation affects the composition of multi-protein complexes, e.g. by phosphorylation-induced conformational changes or the creation of docking sites, e.g. for proteins with SH2, PTB, or WW domains or for 14-3-3 proteins. IP A and IP B stand for interaction partners A and B, respectively. For details refer to text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Potential functional effects of Gab phosphorylation. (A/B) Phosphorylation of one residue affects the phosphorylation of a nearby residue in either a positive or antagonistic fashion. (C) Phosphorylation-induced conformational changes by the cis/trans peptidyl-prolyl-isomerase PIN-1. (D) Phosphorylation affects the composition of multi-protein complexes, e.g. by phosphorylation-induced conformational changes or the creation of docking sites, e.g. for proteins with SH2, PTB, or WW domains or for 14-3-3 proteins. IP A and IP B stand for interaction partners A and B, respectively. For details refer to text.
Mentions: Potential mechanisms that may underpin the action of phosphorylation-dependent positive or negative feedback on Gab proteins are summarized in Fig. 6. Firstly, phosphorylation of a particular residue might affect the phosphorylation of a nearby residue in either a positive or antagonistic fashion, due to phosphorylation-induced changes in protein conformation or simply changes in the electrostatic landscape of the substrate protein [182] (Fig. 6A/B). Secondly, phosphorylation-induced conformational changes may alter the accessibility of key regions, such as the PH domain. These may occur due to electrostatic repulsion/attraction between distinct protein moieties or phosphorylation-induced cis/trans peptidyl-prolyl-isomerisation (Fig. 6C). Although Gab proteins have not been identified as substrates of peptidyl-prolyl-isomerases such as PIN1 yet [183], the high number of phosphorylation sites preceding proline residues and the fact that Gab proteins are targeted by Pro-directed kinases such as ERK support the likelihood of this regulatory mechanism [80,173,175].

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