DOK4 and DOK5: new dok-related genes expressed in human T cells

Favre, C.; Gérard, Audrey; Clauzier, E; Pontarotti, Pierre; Olive, Daniel; Nunès, Jacques A.

doi:10.1038/sj.gene.6363891

Cited by 47 publications

(50 citation statements)

References 29 publications

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“…Dok1 (downstream of tyrosine kinases), or p62Dok1, is a phosphorylated protein downstream of a wide range of protein-tyrosine kinases (PTKs) (Carpino et al, 1997;Yamanashi and Baltimore, 1997;Bhat et al, 1998). Dok1 and the related proteins Dok2, Dok3, Dok4, Dok5 and the insulin receptor substrate (IRS) (Nelms et al, 1998;White, 1998;Cong et al, 1999;Lemay et al, 2000;Di Cristofano et al, 2001;Grimm et al, 2001;Cai et al, 2003;Favre et al, 2003) contain a pleckstrin homology (PH) domain at the N-terminus, a central phosphotyrosine-binding (PTB) domain and a C-terminal domain rich in proline and several tyrosinephosphorylation sites (Carpino et al, 1997;Yamanashi and Baltimore, 1997). After tyrosine-phosphorylation, Dok1 can interact with other signaling molecules containing SH2 domains, such as Ras-GTPase-activating protein (Ras-GAP), SHIP1, Nck, Csk and the X-linked lymphoproliferative syndrome (XLP) gene product SH2D1A (Neet and Hunter, 1995;Noguchi et al, 1999;Sylla et al, 2000;Sattler et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

et al. 2004

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B-cell chronic lymphocytic leukemia (B-CLL) is a malignant disease characterized by an accumulation of monoclonal CD5 þ mature B cells, with a high percentage of cells arrested in the G0/G1 phase of the cell cycle, and a particular resistance toward apoptosis-inducing agents. Dok1 (downstream of tyrosine kinases) is an abundant Ras-GTPase-activating protein (Ras-GAP)-associated tyrosine kinase substrate, which negatively regulates cell proliferation, downregulates MAP kinase activation and promotes cell migration. The gene encoding Dok1 maps to human chromosome 2p13, a region previously found to be rearranged in B-CLL. We have screened the Dok1 gene for mutations from 46 individuals with B-CLL using heteroduplex analysis. A four-nucleotide GGCC deletion in the coding region was found in the leukemia cells from one patient. This mutation causes a frameshift leading to protein truncation at the carboxyl-terminus, with the acquisition of a novel amino-acid sequence. In contrast to the wild-type Dok1 protein, which has cytoplasmic/ membrane localization, the mutant Dok1 is a nuclear protein containing a functional bipartite nuclear localization signal. Whereas overexpression of wild-type Dok1 inhibited PDGF-induced MAP kinase activation, this inhibition was not observed with the mutant Dok1. Furthermore the mutant Dok1 forms heterodimers with Dok1 wild type and the association can be enhanced by Lck-mediated tyrosine-phosphorylation. This is the first example of a Dok1 mutation in B-CLL and the data suggest that Dok1 might play a role in leukemogenesis.

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Section: Introductionmentioning

confidence: 99%

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

et al. 2004

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“…The other Dok proteins, Dok-4 (IRS5), Dok-5 (IRS6), Dok-6 and Dok-7 are mainly expressed in non-haematopoietic cells, notably in neural cells. However, Dok-4 was reported to function as negative regulator in human T cells (Favre et al, 2003).…”

Section: Structure and Cell Expressionmentioning

confidence: 99%

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

Velázquez¹

2012

Hematology - Science and Practice

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“…Recently, two new members of the family were identified: IRS-5 and -6 (also called Dok-4 and -5, respectively). Based on PH and PTB domain sequence identity, IRS-5 and -6 have been shown to be more closely related to each other than to either the IRS or the Dok family (3,4). Dok-6, defined as a novel member of the Dok-4/5 'subclass' of the Dok family (5), and Dok-7 have also recently been identified (6).…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor substrates-5 and -6 are poor substrates for the insulin receptor

Versteyhe

Blanquart²,

Hampe³

et al. 2009

Mol Med Rep

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Abstract. insulin receptor substrates (irS)-5 and -6 are two recently identified members of the IRS family. We investigated their roles as insulin receptor substrates and compared them with Src-homology-2-containing (Shc) protein, a well-established substrate. Bioluminescence resonance energy transfer (BRET) experiments showed no interaction between the receptor and IRS-5, while interaction with IRS-6 was not enhanced by insulin. By contrast, Shc showed an insulin-induced BRET response, as did a truncated form of IRS-1 (1-262). While Shc was heavily phosphorylated after stimulation of the insulin receptor, IRS-5 and -6 showed very weak phosphorylation levels. These results suggest that, although these two adaptors have previously been proposed as substrates for the insulin receptor, they are poor substrates for the insulin receptor. This calls into question their relevance to insulin signalling. IntroductionInsulin is crucial for the regulation of metabolism, growth and development. Binding of insulin to the insulin receptor (IR) leads to the activation of receptor tyrosine kinase and receptor phosphorylation, which enables the binding of docking proteins such as insulin receptor substrates (IRS)-1, -2, -3 and -4 and Src-homology-2-containing protein (Shc). This in turn leads to their phosphorylation and, thereby, intracellular signalling (1).Until recently, the IRS family included IRS-1, -2, -3 and -4 (2) and three downstream of kinases, Dok-1, -2 and -3. These seven proteins have similar amino-terminal pleckstrin homology (PH) and similar phosphotyrosine binding (PTB) and carboxyl-terminal phosphorylation domains which, when tyrosine-phosphorylated, dock Src-homology-2 (SH2) domain proteins. Despite their similar domain architecture, the Dok proteins can be distinguished from the IRS family based on sequence homology and functional interactions. Recently, two new members of the family were identified: IRS-5 and -6 (also called Dok-4 and -5, respectively). Based on PH and PTB domain sequence identity, IRS-5 and -6 have been shown to be more closely related to each other than to either the IRS or the Dok family (3,4). Dok-6, defined as a novel member of the Dok-4/5 'subclass' of the Dok family (5), and Dok-7 have also recently been identified (6).The physiological processes regulated by the Dok family are poorly understood. IRS family members and other receptor tyrosine kinase-associated adaptor molecules are generally involved in signal amplification. Dok-1, -2 and -3 function primarily as inhibitors of tyrosine kinase signalling (7-9). Dok-4 and -5, however, have been shown to be positively involved in tyrosine kinase signalling (3,10-12), although Dok-4 was suggested to be an inhibitor of tyrosine kinase signalling in epithelial cells (13,14). It has been suggested that Dok-4 and -5 are involved in insulin and related insulin-like growth factor (IGF)-I signalling, and play a role as substrates for the insulin and the IGF-I receptor (3). However, contradictory results have been obtained in other studies (13...

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DOK4 and DOK5: new dok-related genes expressed in human T cells

Cited by 47 publications

References 29 publications

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

Insulin receptor substrates-5 and -6 are poor substrates for the insulin receptor

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