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.
Highlights
In this review, we provide a detailed overview of the structure, effector functions, regulation and evolution of the Gab/Daughter of Sevenless (DOS) family
Phospho-tyrosine residues within the cytoplasmic tails of these receptors serve as docking sites for the SH2 and/or PTB domains of growth factor receptor bound protein 2 (Grb2), which binds to the proline-rich regions in Grb2 associated binder 1 (Gab1)-3 via its C-terminal SH3 domain [11,33,35,36,37,38,39,40]
A third mechanism by which docking proteins can be negatively regulated by protein phosphorylation is via changes in their "social behaviour", alterations in their ability to interact with crucial interaction partners or in their subcellular localisation (Fig. 6D; [4]). Key mediators of this kind of mechanism are 14-3-3 proteins, a highly- conserved and ancient group of eukaryotic adaptor proteins that bind to specific phospho-Ser/Thrresidues in their client proteins and thereby execute the effect of phosphorylation events, either by stabilizing certain protein conformations or regulating intermolecular protein-protein interactions [2]. Several docking proteins such as kinase suppressor of ras (KSR), SLP-76 and IRS proteins have been described as 14-3-3 client proteins [4,15,181] and we recently reported that Gab2 interacts with 14-3-3 proteins in a phosphorylation-dependent manner [49]
Summary
Gab docking proteins have emerged as critical players in many physiological processes as well as pathologies such as cancer and inflammatory diseases. In order to fully understand the signalling roles of Gab proteins, it is clear that various disciplines will need to cooperate and utilize a systems-based approach that integrates structural and biophysical studies on regulation of protein-protein interactions, mathematical and computational modelling of the Gab signalling network and functional analyses that exploit the genetics of appropriate model organisms. Such an endeavour is likely to provide exciting new insights into the mechanisms and functions of Gab signalosomes. Aa: Amino acid; AD: Alzheimer's disease; AML: Acute myeloid leukemia; BCR: B cell antigen receptor; Bcr: Breakpoint cluster region; bFGF: Basic fibroblast growth factor; BMMCs: Bone marrow derived mast cells; BTAM: Bi-phosphoryl tyrosine activation motif; BTK: Bruton's tyrosine kinase; CBP: Csk-binding protein; CD: Cluster of differentiation; CFC: Cardio-facious-cutaneous syndromes; CML: Chronic myeloid leukemia; CNS: Central nervous system; Crk: Sarcoma virus CT10 oncogene homolog; CS: Costello syndrome; CSF: Colony stimulating factor; CSW: Corkscrew; DAG: Diacylglycerol; DNA: Deoxyribonucleic acid; DOS: Daughter of sevenless; EGF: Epidermal growth factor; ERK: Extracellular signal regulated kinase; EST: Expressed sequence tag; EPO: Erythropoietin; FGF: Fibroblast growth factor; FRS: Fibroblast growth factor receptor substrate; Gab: Grb2-associated binder; GADS: Grb2-related adaptor downstream of Shc; GAP: GTPase activating protein; Grb: Growth factor receptor-bound protein 2; Gsk: Glycogen synthase kinase; GST: Glutathione S-transferase; GTP: Guanine nucleotide trisphosphate; HER: Human epidermal growth factor receptor; HGF: Hepatocyte growth factor; IL: Interleukin; IP3: Inositoltrisphosphate; IRS: Insulin receptor substrate; JAK: Janus kinase/Just another kinase; JMML: Juvenile myelomonocytic leukemia; kDa: Kilodalton; KSR: Kinase suppressor of ras; LAT: Linker of activated T cells; LPA: Lysophosphatidic acid; LS: LEOPARD syndrome (multiple lentigines: electrocardiographic conduction defects; ocular hypertelorism; pulmonary stenosis; abnormalities of the genitalia; retardation of growth and sensorineural deafness); MAPK: Mitogen activated protein kinase; MBD: Met binding domain; MEFs: Mouse embryonic fibroblasts; MEK: Mitogen activated protein/extracellular signal regulated kinase kinase; MONA: Monocytic adaptor; NCFC: Neuro-cardio-facious-cutaneous syndromes; NF: Neurofibromatosis; NF- B: Nuclear Factor kappa B; NGF: Nerve growth factor; NK: Natural killer; NRG: Neuregulin; NS: Noonan syndrome; PAG: Phosphoprotein associated with glycosphingolipid-enriched microdomains; PAK: p21-activated kinase; PDGF: Platelet-derived growth factor; PH: Pleckstrin homology; PI3K: Phosphatidyl-inositol-3 kinase; PI3KCA: gene encoding the catalytic subunit of phosphatidyl-inositol-3 kinase; PIP: Phosphatidylinositol-phosphate; PKB: Protein kinase B; PLC: Phospholipase; PTB: Phospho-tyrosine binding; PTEN: Phosphatase and Tensin homolog; PTK: Protein tyrosine kinase; PTP: Protein tyrosine phosphatase; PTPN: Protein tyrosine phosphatase: non-receptor; Raf: Rapidly growing fibrosarcoma; RANK: Receptor Activator of NF- B; Ras: Rat sarcoma; RNA: Ribonucleic acid; RNAi: RNA interference; ROK: Rho kinase; RTK: Receptor tyrosine kinase; SCF: Stem cell factor; Sea: S13 erythroblastosis oncogene homolog; siRNA: Small interfering RNA; SH2: Src homology 2; SH3: Src homology 3; SHIP: SH2-containing inositol 5-phosphatase; SHP: SH2 domain-containing proteintyrosine phosphatase; SLP: SH2 domain containing leukocyte protein; SOC: Suppressor of clear; Src: Sarcoma http://www.biosignaling.com/content/7/1/22 viral oncogene homolog; STAT: Signal transducer and activator of transcription; Syk: Spleen tyrosine kinase; ZAP-70: Zeta-chain associated protein of 70 kDa
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