Expression of Splice Variants of the Human ADAM15 Gene and Strong Interaction between the Cytoplasmic Domain of One Variant and Src Family Proteins Lck and Hck

Yasui, Atsushi; Matsuura, Keiko; Shimizu, Eiichi; Hijiya, Naoki; Higuchi, Yasunori; Yamamoto, Shunsuke

doi:10.1159/000078672

Cited by 8 publications

(11 citation statements)

References 29 publications

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“…We and others have shown previously that the ADAM-15 cytoplasmic domains are capable of associating with diverse SH3-and SH2-domain containing proteins, including Grb2, MAD2, endophilin, Tks5/Fish, and Src family protein-tyrosine kinases (17,18,31,40). These associations, plus others with additional SH3 domain proteins, have recently been confirmed in a phage display analysis (41).…”

Section: Discussionmentioning

confidence: 52%

“…However, differences were clearly apparent for the interaction with Src and with the adaptor protein Nck, which were bound more effectively by ADAM-15B. Yasui et al (40) have also reported similar findings for the preferential interaction of ADAM-15C (in their terminology, ADAM15v2) with the Src family protein tyrosine kinases Lck and Hck compared with ADAM-15A (ADAM15v). At present, the molecular basis for these interactions are unknown but mutational studies with ADAM-15A have shown that Grb2 binding involves the COOH-terminal portion of the cytoplasmic domain, whereas Lck interaction involved the membraneproximal part (18).…”

Section: Discussionmentioning

confidence: 66%

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Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Zhong

Poghosyan

Pennington

et al. 2008

Molecular Cancer Research

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Adamalysins [a disintegrin and metalloproteinase (ADAM)] are a family of cell surface transmembrane proteins that have broad biological functions encompassing proteolysis, adhesion, and cell signal regulation. We previously showed that the cytoplasmic domain of ADAM-15 interacts with Src family protein tyrosine kinases and the adaptor protein growth factor receptor binding protein 2 (Grb2). In the present study, we have cloned and characterized four alternatively spliced forms of ADAM-15, which differ only in their cytoplasmic domains. We show that the four ADAM-15 variants were differentially expressed in human mammary carcinoma tissues compared with normal breast. The expression of the individual isoforms did not correlate with age, menopausal status, tumor size or grade, nodal status, Nottingham Prognostic Index, or steroid hormone receptor status. However, higher levels of two isoforms (ADAM-15A and ADAM-5B) were associated with poorer relapse-free survival in node-negative patients, whereas elevated ADAM-15C correlated with better relapse-free survival in node-positive, but not in node-negative, patients. The expression of ADAM-15A and ADAM-15B variants in MDA-MB-435 cells had differential effects on cell morphology, with adhesion, migration, and invasion enhanced by expression of ADAM-15A, whereas ADAM-15B led to reduced adhesion. Using glutathione S-transferase pull-down assays, we showed that the cytoplasmic domains of ADAM-15A, ADAM-15B, and ADAM-15C show equivalent abilities to interact with extracellular signal-regulated kinase and the adaptor molecules Grb2 and Tks5/Fish, but associate in an isoform-specific fashion with Nck and the Src and Brk tyrosine kinases. These data indicate that selective expression of ADAM-15 variants in breast cancers could play an important role in determining tumor aggressiveness by interplay with intracellular signaling pathways. (Mol Cancer Res 2008;6(3):383 -94)

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 66%

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Zhong

Poghosyan

Pennington

et al. 2008

Molecular Cancer Research

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“…Experimental studies showed that the ADAM-12 level is associated with cancer through degradation of extracellular matrix, as well as regulation of cell proliferation and apoptosis [46,47] . Earlier studies showed that the cytoplasmic parts of ADAM-12 and ADAM-15 interact with Src homology 3 domain to exert their actions [48,49] .…”

Section: Discussionmentioning

confidence: 99%

Aberrant Expression of Disintegrin-Metalloprotease Proteins in the Formation and Progression of Uterine Cervical Cancer

Shaker

Yokoyama²,

Mori³

et al. 2011

Pathobiology

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Objective: Dysregulated expression of disintegrin-metalloprotease proteins [a disintegrin and metalloproteases (ADAMs) and ADAMs with thrombospondin motif (ADAMTSs)] has been reported in many types of cancers and is believed to play an important role in cancer formation and metastasis. However, little is known about the expression of ADAMs and ADAMTSs in the development of human cervical cancer. Methods: Reverse transcriptase polymerase chain reaction and immunoblotting were performed to assess the expression of several disintegrin-metalloproteases and tissue inhibitors of metalloproteinases (TIMPs) in squamous-type cervical cancer cells and oncogenically modified keratinocytes (immortalized human cervical keratinocytes transduced with human papilloma virus-16 E6/E7 proteins with or without oncogenes). Immunohistochemistry of ADAM-9, ADAM-10 and TIMP-3 was performed on 31 primary human cervical tissue specimens of preinvasive and invasive cervical carcinoma. Results: mRNA levels of ADAM-9, ADAM-10, ADAM-12, TIMP-2 and TIMP-3 were upregulated as cervical cells progressed from dysplastic to malignant lesions compared to normal cervical cells. These results were corroborated at the protein level by Western blot analysis and immunohistochemistry. Conclusion: The expression of disintegrin-metalloproteases and their endogenous regulators was dysregulated during cervical carcinogenesis. The aberrant expression of ADAMs might contribute to the pathogenesis of cervical cancer formation and progression.

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“…ADAM15 cDNA was cloned from a human breast cancer cell line [27]. Malignant hematological and tissue-derived cell lines express ADAM15 mRNA and known splice variants [48,49]. There is a markedly strong upregulation of ADAM15 in chondrosarcomas compared with adult normal articular cartilage [4].…”

Section: Discussionmentioning

confidence: 99%

Expression of ADAM15 in lung carcinomas

et al. 2005

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ADAM15, a member of the ADAM (a disintegrin and metalloprotease) family, is a membrane protein containing both protease and adhesion domains and may, thus, be involved in tumor invasion and metastasis. The aim of this study was to analyze the expression of ADAM15 and its potential ligand, integrin alpha(v)beta3 (CD51/CD61), in lung carcinoma cell lines and tissues. Most small cell lung carcinomas (SCLCs) and non-SCLC cell lines were ADAM15, alpha(v) and beta3 integrin mRNA positive. Half of the cell lines expressed ADAM15, and three expressed the alpha(v)beta3 heterodimer at the cell surface as shown using flow cytometry. Paraffin sections of pulmonary epithelial tumors, including SCLCs (n=26), squamous cell cancer (SCCs, n=27) and adenocarcinomas (ACs, n=17) were stained with antibodies to the ectosolic and cytosolic domain of ADAM15 and alpha(v)beta3 integrin complex. The results were scored (0-12, according to Remmele's score). Normal epithelial cells of the lung were negative or slightly positive for ADAM15 (score<2). The score was always significantly higher for tumor cells. ACs showed the strongest staining (tumor center; ADAM15ecto; mean+/-SEM; 5.47+/-1.04), whereas SCLCs only showed weak ADAM15 expression (2.67+/-0.42; SCCs: 3.62+/-0.62). Frequently, significantly stronger ADAM15 expression has been shown in tumor cells located at the front of invasion compared with those within solid formations. Overall analysis of all tumor specimens and each tumor type revealed no significant correlation between tumor stage or degree of differentiation and ADAM15 ectosolic or cytosolic domain expression in tumor cells. Both molecules are often co-localized in the same tumor cells in ADAM15- and alpha(v)beta3 integrin-positive carcinomas. In summary, lung carcinoma cell lines and tissues were frequently ADAM15 positive.

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Expression of Splice Variants of the Human ADAM15 Gene and Strong Interaction between the Cytoplasmic Domain of One Variant and Src Family Proteins Lck and Hck

Cited by 8 publications

References 29 publications

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

Aberrant Expression of Disintegrin-Metalloprotease Proteins in the Formation and Progression of Uterine Cervical Cancer

Expression of ADAM15 in lung carcinomas

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