Cell cycle-dependent phosphorylation of Disabled-2 by cdc2

He, Junqi; Xu, Jianguo; Xu, Xiang Xi; Hall, Randy A.

doi:10.1038/sj.onc.1206767

Cited by 39 publications

(30 citation statements)

References 37 publications

(62 reference statements)

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“…The decrease in DAB2 during the luteal phase could partly be explained by altered cdc2 protein levels. Previous studies have indicated that functional BRCA1 indirectly inhibits cdc2 kinase activity (51), which then negatively regulates DAB2 through cell cycle -specific phosphorylation (52). Absence of functional BRCA proteins would therefore lead to accumulation of active cdc2 and subsequent reduction of DAB2.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Tone

Begley²,

Sharma

et al. 2008

Clinical Cancer Research

125

113

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Purpose:To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa. Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa. Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription^PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples. Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.

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Section: Resultsmentioning

confidence: 99%

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Tone

Begley²,

Sharma

et al. 2008

Clinical Cancer Research

125

113

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“…In support of this idea, several endocytic proteins including disabled-2 (Dab2), dynamin II (dynII), epsin, eps15, a-adaptin and amphiphysin II, are inactivated by Cdk1-mediated phosphorylation during mitosis (Chen et al, 1999;Chircop et al, 2010;Dephoure et al, 2008;He et al, 2003;Kariya et al, 2000). Furthermore, clathrin, epsin and cyclin-Gassociated kinase (GAK) have been shown to play non-endocytic roles in chromosome alignment and segregation during mitosis (Liu and Zheng, 2009;Royle et al, 2005;Shimizu et al, 2009).…”

Section: Introductionmentioning

confidence: 97%

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

Maggie

Chircop

2012

Journal of Cell Science

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SummaryMitosis involves considerable membrane remodelling and vesicular trafficking to generate two independent cells. Consequently, endocytosis and endocytic proteins are required for efficient mitotic progression and completion. Several endocytic proteins also participate in mitosis in an endocytosis-independent manner. Here, we report that the sorting nexin 9 (SNX9) subfamily members -SNX9, SNX18 and SNX33 -are required for progression and completion of mitosis. Depletion of any one of these proteins using siRNA induces multinucleation, an indicator of cytokinesis failure, as well as an accumulation of cytokinetic cells. Time-lapse microscopy on siRNA-treated cells revealed a role for SNX9 subfamily members in progression through the ingression and abscission stages of cytokinesis. Depletion of these three proteins disrupted MRLC S19 localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge between nascent daughter cells. SNX9 depletion also disrupted the localization of Golgi during cytokinesis. Endocytosis of transferrin was blocked during cytokinesis by depletion of the SNX9 subfamily members, suggesting that these proteins participate in cytokinesis in an endocytosis-dependent manner. In contrast, depletion of SNX9 did not block transferrin uptake during metaphase but did delay chromosome alignment and segregation, suggesting that SNX9 plays an additional non-endocytic role at early mitotic stages. We conclude that SNX9 subfamily members are required for mitosis through both endocytosis-dependent and -independent processes.

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“…To date, protein kinase C (PKC) and Cdc2 are the only two known DAB2 kinases (14,15). The major PKC phosphorylation site has been mapped to Ser 24 .…”

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confidence: 99%

Disabled-2 Is a Negative Regulator of Integrin αIIbβ3-mediated Fibrinogen Adhesion and Cell Signaling

Huang¹,

Cheng

Liao

et al. 2004

Journal of Biological Chemistry

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Disabled-2 (DAB2) is an adapter protein that is up-regulated during megakaryocytic differentiation of hematopoietic cells and is abundantly expressed in platelets. In this study, the role of DAB2 in integrin ␣ IIb ␤ 3 -mediated matrix protein fibrinogen adhesion and cell signaling was investigated. In K562 cells differentiating to the megakaryocytic lineage, down-regulation of DAB2 by DAB2 small interfering RNA augmented integrin ␣ IIb ␤ 3 activation and resulted in an increase in cell adhesion to fibrinogen. Ectopic expression of DAB2 reversed the DAB2 small interfering RNA effect or, by itself, decreased fibrinogen adhesion of K562 cells. Mutational analysis revealed that a DAB2 Ser 24 phosphorylation mutant (S24A) abrogated the inhibitory function of DAB2. The spatial and temporal association/interaction of DAB2 and platelet integrin ␣ IIb ␤ 3 (CD61) in both megakaryocytic cells and platelets led us to examine the effect of Ser 24 phosphorylation on the interaction between DAB2 and integrin ␤ 3 . Through cellular localization and co-immunoprecipitation analysis, we demonstrate for the first time that Ser 24 phosphorylation promotes membrane translocation of DAB2 and its subsequent interaction with integrin ␤ 3 , thereby defining a mechanism for DAB2 in regulating integrin ␣ IIb ␤ 3 activation and inside-out signaling. Consistent with the effect on fibrinogen adhesion, Ser 24 phosphorylation of DAB2 was also involved in the negative regulation of ␣ IIb ␤ 3 -induced T cell factor transcriptional activity. In contrast, the S24A mutant acted like wild-type DAB2 and inhibited both ␤-catenin-and plakoglobin-mediated T cell factor transactivation. Hence, DAB2 elicits distinct regulatory mechanisms in ␣ IIb ␤ 3 and ␤-catenin/plakoglobin signaling in a Ser 24 phosphorylation-dependent and -independent manner, respectively. These findings indicate Ser 24 phosphorylation as a molecular basis for DAB2 acting as a negative regulator in ␣ IIb ␤ 3 inside-out signaling and contribute to our understanding of DAB2 in megakaryocytic differentiation and platelet function.Disabled-2 (DAB2) is an adapter protein that has been implicated in growth factor signaling (1, 2), endocytosis (3-5), cell adhesive function (6, 7), and hematopoietic cell differentiation (8). Like other adapter proteins, DAB2 elicits its function through interaction with other cellular proteins. DAB2 interacts with Grb2, myosin VI, SMAD2/3, DIP1/2, Dvl-3, the integrin ␤ subunit, and c-Src through the N-terminal phosphotyrosine-binding (PTB) 1 domain and the C-terminal proline-rich region (1, 4, 5, 9 -13). These interactions have been shown to modulate cytoskeleton organization, transcriptional activity, and cell signaling of various receptor protein-tyrosine kinases. DAB2 thus plays in a pivotal role in the control of cellular homeostasis.In cells, protein phosphorylation of DAB2 modulates its functional activity during growth factor signaling, megakaryocytic differentiation, macrophage spreading, and cell cycle progression. To date, protein kinase C (PKC) and...

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Cell cycle-dependent phosphorylation of Disabled-2 by cdc2

Cited by 39 publications

References 37 publications

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis

Disabled-2 Is a Negative Regulator of Integrin αIIbβ3-mediated Fibrinogen Adhesion and Cell Signaling

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