Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

Xu, Xiang Xi; Yi, Taolin; Tang, Bo; Lambeth, J. David

doi:10.1038/sj.onc.1201678

Cited by 116 publications

(125 citation statements)

References 27 publications

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“…The suppressive activity of Dab2 for MAPK activation and c-fos expression is reverted by plating the cells on matrix gel (Figure 7b). The ®nding that Dab2 suppresses c-fos expression is consistent with our previous results that Dab2 binds Grb2 competing with the recruitment of Sos, and thus suppresses Ras activation (Xu et al, 1998).…”

Section: Dab2 Suppresses Mapk Activation and C-fos Expressionsupporting

confidence: 92%

“…In previous studies, we have shown that Dab2 competes with Sos for binding to Grb2, and thus may act as a negative regulator of the Ras mitogenic signaling pathway (Xu et al, 1998). We found that in NIH:OVCAR-3 ovarian cancer cells expression of Dab2 by recombinant adenovirus suppresses c-fos expression, a downstream target of the Ras mitogenic pathway (Figure 7a).…”

Section: Dab2 Suppresses Mapk Activation and C-fos Expressionmentioning

confidence: 65%

“…Dab2 may negatively regulate cell growth by constraining Ras activation by sequestering Grb2 from the Grb2/ Sos complex (Xu et al, 1998). Here we have shown that expression of Dab2 by adenovirus-mediated transfection suppresses MAPK activation and c-fos expression, two downstream targets of the Ras pathway.…”

Section: Discussionmentioning

confidence: 77%

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Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells

et al. 2000

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Section: Dab2 Suppresses Mapk Activation and C-fos Expressionsupporting

confidence: 92%

Section: Dab2 Suppresses Mapk Activation and C-fos Expressionmentioning

confidence: 65%

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Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells

et al. 2000

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“…Loss of DOC-2 is believed to be an early step in malignant cell transformation in ovarian cancer (Fazili et al, 1999). DOC-2 binds to the SH3 motives of Grb2/Sos through its proline-rich domains, thus enhancing the dissociation of the Grb2/Sos complex (Xu et al, 1998), which functions as an intermediary between, for example, activated tyrosine kinase growth factor receptors and the Ras/Raf MAP kinase cascade. Because Grb2/Sos dissociation blocks growth factor-induced mitogenesis, DOC-2 was suggested to function as a tumor suppressor, an assumption that has also been supported by transfection experiments in ovarian cancer and choriocarcinoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…The structure of DOC-2 includes a highly conserved phosphotyrosine-interacting domain at the amino terminus, suggesting its potential interaction with other proteins (Bork and Margolis, 1995;Kavanaugh and Williams, 1994). Moreover, both proteins have proline-rich domains at the carboxy terminus (Ren et al, 1993) that can bind to the SH3 motive of Grb2, thus sequestering Grb2 from the Sos/Grb2 complex (Xu et al, 1998). Because this complex is important for the activation of K-ras, the dissociation of Sos/Grb2 may lead to decreased activation of K-ras.…”

Section: Doc-2/hdab2mentioning

confidence: 99%

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Huang

Friess

Kleeff

et al. 2001

Laboratory Investigation

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SUMMARY:DOC-2/hDab2 (DOC-2) has tumor suppressive functions in ovarian cancer and choriocarcinoma. In these tumors, it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. Pancreatic cancer exhibits a high frequency of K-ras gene mutations; however, it is not known whether DOC-2 expression is altered in these tumors. Therefore, we investigated DOC-2 expression in 22 pancreatic adenocarcinomas and in 6 pancreatic cancer cell lines. Findings in human tumors were compared with normal controls and correlated with clinicopathological data. Additionally, the influence of K-ras on DOC-2 transcription was investigated. Northern blot and Western blot analyses both demonstrated an increase of DOC-2 mRNA and protein levels in primary pancreatic cancers in comparison with normal controls. In situ hybridization showed DOC-2 mRNA expression in the majority of cancer cells of primary tumors, as well as in chronic pancreatitis-like lesions surrounding the cancer mass. Immunohistochemistry mirrored the in situ hybridization findings. In contrast, levels of expression of DOC-2 in lymph node metastases were markedly decreased in comparison with levels in primary tumors. In addition, in 5 metastatic pancreatic cancer cell lines, DOC-2 mRNA and protein levels were low, whereas quantitative RT-PCR demonstrated relatively higher levels in a nonmetastatic pancreatic cancer cell line. In conclusion, DOC-2 is overexpressed in primary pancreatic adenocarcinoma but down-regulated in metastatic disease, suggesting a tumor suppressor function of DOC-2 in the late steps of pancreatic carcinogenesis. (Lab Invest 2001, 81:863-873).P ancreatic adenocarcinomas are the fourth or fifth leading cause of cancer-related death in developed countries, with an average 5-year survival rate of less than 0.5% (Gudjonsson, 1995). The poor prognosis of pancreatic cancer manifests itself by low resection rates, nonresponsiveness to adjuvant or palliative therapy, and a high incidence of recurrence and early metastasis formation following potentially curative resection.It is known that various genetic and epigenetic alterations are involved in the pathogenesis of pancreatic cancer, including overexpression of mitogenic growth factors and growth factor receptors (Friess et al, 1993;Korc et al, 1992), as well as mutations of the K-ras proto-oncogene and p53 and Smad4 tumor suppressor genes (Friess et al, 1998). A better understanding of the underlying molecular mechanisms, including those related to metastasis in this malignancy, will hopefully contribute to improvement of early diagnosis and effective therapy in the future. DOC-2/hDab2(DOC-2) is a candidate tumor suppressor gene that was first isolated by differential RNA display techniques (Liang and Pardee, 1992;Mok et al, 1994). In 1995, Albertsen and coworkers (Albertsen et al, 1996) reported the complete gene sequence of the 3.2-kb DOC-2 transcript and its localization at chromosome 5p13. It was shown that DOC-2 is the human homolog of mouse Dab2, which was cloned f...

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Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity

Yang

Smith

Cohen

et al. 2002

Cancer

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The loss of Dab2 is closely associated with the transition of ovarian surface epithelial cells to premalignant states and is likely involved in the initiation of ovarian tumorigenicity. Transient loss of collagen IV and laminin in the basement membrane of the premalignant epithelium and subsequent inactivation of Dab2 are common early events associated with tumorigenicity of the ovarian surface epithelium.

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Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

Cited by 116 publications

References 27 publications

Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells

Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity

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