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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

Recruitment of Gab proteins to activated receptors and the main effector arms of Gab signalling. The indirect mode of recruitment applies to all receptors except c-Met (see text and Fig. 3 for details). Characteristics of this mechanism are that phosphotyrosine residues within the cytoplasmic tails of activated surface receptors serve as docking sites for the SH2 domain of Grb2, which in turn binds via its C-terminal SH3 domain to specific binding sites in Gab1-3. Alternatively, Shc can serve as additional bridging molecules between Gab and activated receptors. Membrane/receptor association leads to tyrosine phosphorylation of Gab proteins and subsequent recruitment of SH2 domain-containing effectors such as SHP2, p85, PLCγ and Crk. While it has been shown by numerous studies that the association between Gab proteins and the effectors Shp2, p85, Grb2, Crk and PLCγ represents a direct protein-protein interaction, the coupling between Gab and STAT5 needs to be resolved in the future.
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Figure 2: Recruitment of Gab proteins to activated receptors and the main effector arms of Gab signalling. The indirect mode of recruitment applies to all receptors except c-Met (see text and Fig. 3 for details). Characteristics of this mechanism are that phosphotyrosine residues within the cytoplasmic tails of activated surface receptors serve as docking sites for the SH2 domain of Grb2, which in turn binds via its C-terminal SH3 domain to specific binding sites in Gab1-3. Alternatively, Shc can serve as additional bridging molecules between Gab and activated receptors. Membrane/receptor association leads to tyrosine phosphorylation of Gab proteins and subsequent recruitment of SH2 domain-containing effectors such as SHP2, p85, PLCγ and Crk. While it has been shown by numerous studies that the association between Gab proteins and the effectors Shp2, p85, Grb2, Crk and PLCγ represents a direct protein-protein interaction, the coupling between Gab and STAT5 needs to be resolved in the future.

Mentions: Docking proteins of the Gab family use several different mechanisms to regulate their subcellular localization. Firstly, the PH domain confers recruitment of Gab proteins to plasma membrane patches enriched in specific phosphatidyl-inositol-phosphates (PIPs) [23-29]. In addition to the PH domain, Gab proteins use at least two additional mechanisms for their recruitment to activated plasma membrane-associated receptors. The first mechanism appears unique to the c-Met/Gab1 receptor/transducer system. Gab1 contains a specific c-Met binding domain (MBD), which encompasses aa residues 450 to 532 and confers the direct interaction between this docking protein and the c-MET RTK following its engagement by its ligand, hepatocyte growth factor (HGF) [17,30-32]. The MBD could be narrowed down to a sixteen amino acid motif (aa residues 486-501) called Met binding motif [31]. This direct interaction involves the activated kinase domain of c-MET and the MBD in Gab1 [17,31]. However, c-MET also recruits Gab1 via a second mechanism involving the small adaptor protein Grb2, and this represents the only mode of receptor interaction for Gab2 [33]. The significance of this indirect recruitment is underscored by the observation that a c-Met receptor mutant selectively defective in Grb2 binding fails to induce branching morphogenesis in the Madin-Darby canine kidney (MDCK) cell line model system [34] and by the non-viable phenotype of knock-in mice expressing a Grb2 binding-deficient Gab1 mutant [32]. This indirect mode of recruitment (Figs. 2 and 3) appears to apply to all other receptors recruiting Gab proteins. Phospho-tyrosine residues within the cytoplasmic tails of these receptors serve as docking sites for the SH2 and/or PTB domains of Grb2, which binds to the proline-rich regions in Gab1-3 via its C-terminal SH3 domain [11,33,35-40]. Shc proteins can serve as additional bridging adaptors between Grb2 and the tyrosine-phosphorylated receptors.


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

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

Recruitment of Gab proteins to activated receptors and the main effector arms of Gab signalling. The indirect mode of recruitment applies to all receptors except c-Met (see text and Fig. 3 for details). Characteristics of this mechanism are that phosphotyrosine residues within the cytoplasmic tails of activated surface receptors serve as docking sites for the SH2 domain of Grb2, which in turn binds via its C-terminal SH3 domain to specific binding sites in Gab1-3. Alternatively, Shc can serve as additional bridging molecules between Gab and activated receptors. Membrane/receptor association leads to tyrosine phosphorylation of Gab proteins and subsequent recruitment of SH2 domain-containing effectors such as SHP2, p85, PLCγ and Crk. While it has been shown by numerous studies that the association between Gab proteins and the effectors Shp2, p85, Grb2, Crk and PLCγ represents a direct protein-protein interaction, the coupling between Gab and STAT5 needs to be resolved in the future.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Recruitment of Gab proteins to activated receptors and the main effector arms of Gab signalling. The indirect mode of recruitment applies to all receptors except c-Met (see text and Fig. 3 for details). Characteristics of this mechanism are that phosphotyrosine residues within the cytoplasmic tails of activated surface receptors serve as docking sites for the SH2 domain of Grb2, which in turn binds via its C-terminal SH3 domain to specific binding sites in Gab1-3. Alternatively, Shc can serve as additional bridging molecules between Gab and activated receptors. Membrane/receptor association leads to tyrosine phosphorylation of Gab proteins and subsequent recruitment of SH2 domain-containing effectors such as SHP2, p85, PLCγ and Crk. While it has been shown by numerous studies that the association between Gab proteins and the effectors Shp2, p85, Grb2, Crk and PLCγ represents a direct protein-protein interaction, the coupling between Gab and STAT5 needs to be resolved in the future.
Mentions: Docking proteins of the Gab family use several different mechanisms to regulate their subcellular localization. Firstly, the PH domain confers recruitment of Gab proteins to plasma membrane patches enriched in specific phosphatidyl-inositol-phosphates (PIPs) [23-29]. In addition to the PH domain, Gab proteins use at least two additional mechanisms for their recruitment to activated plasma membrane-associated receptors. The first mechanism appears unique to the c-Met/Gab1 receptor/transducer system. Gab1 contains a specific c-Met binding domain (MBD), which encompasses aa residues 450 to 532 and confers the direct interaction between this docking protein and the c-MET RTK following its engagement by its ligand, hepatocyte growth factor (HGF) [17,30-32]. The MBD could be narrowed down to a sixteen amino acid motif (aa residues 486-501) called Met binding motif [31]. This direct interaction involves the activated kinase domain of c-MET and the MBD in Gab1 [17,31]. However, c-MET also recruits Gab1 via a second mechanism involving the small adaptor protein Grb2, and this represents the only mode of receptor interaction for Gab2 [33]. The significance of this indirect recruitment is underscored by the observation that a c-Met receptor mutant selectively defective in Grb2 binding fails to induce branching morphogenesis in the Madin-Darby canine kidney (MDCK) cell line model system [34] and by the non-viable phenotype of knock-in mice expressing a Grb2 binding-deficient Gab1 mutant [32]. This indirect mode of recruitment (Figs. 2 and 3) appears to apply to all other receptors recruiting Gab proteins. Phospho-tyrosine residues within the cytoplasmic tails of these receptors serve as docking sites for the SH2 and/or PTB domains of Grb2, which binds to the proline-rich regions in Gab1-3 via its C-terminal SH3 domain [11,33,35-40]. Shc proteins can serve as additional bridging adaptors between Grb2 and the tyrosine-phosphorylated receptors.

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