Structure and expression of the murine ADAM 15 gene and its splice variants, and difference of interaction between their cytoplasmic domains and Src family proteins

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

doi:10.1016/j.bbrc.2003.08.070

Cited by 14 publications

(17 citation statements)

References 25 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: Discussionsupporting

confidence: 53%

“…Equivalent isoforms have been observed in the analysis done by Ortiz et al (25). The ADAM-15D isoform was also observed in studies on human intestinal epithelial cells (30), and the ADAM-15A, ADAM-15B, and ADAM-15C variants were observed in hematopoietic cell types (31). A recent study documented 13 splice variants involving the ADAM-15 cytoplasmic domain (29), which result both from different exon usage and alternative splice sequences in two exons (exons 20 and 21).…”

Section: Expression Of Variant Adam15 Isoforms In Breast Cancer and Tmentioning

confidence: 67%

“…This isoform also decreased cell attachment, which may contribute to the lower Matrigel invasion capabilities of ADAM-15B -expressing cells compared with the ADAM-15A cells. There is substantial evidence that ADAM-15 can influence both cell adhesion and migration (31,36,37). Interactions of ADAM-15 disintegrin domain with integrins a v h 3 , a 5 h 1 , and a 9 h 1 have been documented (5)(6)(7), and these may in principle occur either in trans, regulating cell-cell adhesion, or in cis, thereby modulating cell interactions with matrix substrata.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 53%

Section: Expression Of Variant Adam15 Isoforms In Breast Cancer and Tmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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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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“…Based on this and on the findings of Davuluri et al [24], it was assumed that the human ADAM15 cDNA sequence (U41767) was truncated at its 5′ end. Recent additions to the database (NCBI NM_207197) indicate that each of the six ADAM15 transcript variants has a 5′-UTR of 101 nucleotides [25]. Our findings and those of Kleino et al [18] confirm that the UTR of ADAM15 is at least 58 bp and could be up to 159 bases, with Kleino et al suggesting several possible TSS.…”

Section: Discussionsupporting

confidence: 80%

Characterisation of the Human ADAM15 Promoter

Khammas

Bowen

Williams

et al. 2010

Nephron Exp Nephrol

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Background: ADAM15 is a membrane-bound member of the adamalysin family that is up-regulated in areas of tissue remodelling. Previous studies have demonstrated the role of ADAM15 in mesangial cell migration, which is integral in tissue remodelling in pathology and repair. The current study was designed to identify and analyse the genomic regions upstream of ADAM15 that would regulate its transcription. Methods: Using 5′-RACE and RT-PCR, the ADAM15 5′-UTR was extended and luciferase constructs assembled to examine the transcription start site and characterise the promoter region of this gene. Results: A 145-bp proximal promoter construct showed full activity in unstimulated cells. Analysis of this region identified three potential Sp1-binding sites. Electromobility and supershift assays confirmed that Sp1 was constitutively present in MC nuclei. Mutations in each Sp1 site confirmed each was needed for full activity, while mutation of all three sites abrogated luciferase activity demonstrating that Sp1 was involved in the promoter activity of ADAM15. Methylation of this promoter fragment abolished the activity, while the methyltransferase inhibitor 5-aza-3′-deoxycytidine showed no increased activity in transfected cells, implying that the promoter was not methylated in our cells. Conclusion: These results demonstrate the intrinsic promoter activity of ADAM15 in quiescent MC and show the involvement of Sp1 in its regulation.

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“…ADAM15v2 protein markedly enhanced binding with Lck in T lymphocytes (49). ADAM12 has been demonstrated to become phosphorylated at the C-terminal Tyr901 in vitro and in cultured cells by v-Src (50).…”

Section: Figmentioning

confidence: 99%

Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ϵ

Sundberg

Thodeti

Kveiborg

et al. 2004

Journal of Biological Chemistry

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The ADAM (a disintegrin and metalloprotease) family consists of multidomain cell-surface proteins that have a major impact on cell behavior. These transmembraneanchored proteins are synthesized as proforms that have (from the N terminus): a prodomain; a metalloprotease-, disintegrin-like-, cysteine-rich, epidermal growth factor-like, and transmembrane domain; and a cytoplasmic tail. The 90-kDa mature form of human ADAM12 is generated in the trans-Golgi through cleavage of the prodomain by a furin-peptidase and is stored intracellularly until translocation to the cell surface as a constitutively active protein. However, little is known about the regulation of ADAM12 cell-surface translocation. Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern. We report that protein kinase C (PKC) ⑀ induces ADAM12 translocation to the cell surface and that catalytic activity of PKC⑀ is required for this translocation. Cells possess a diverse array of surface proteins, lipids, and carbohydrates that provide active gateways for the selective intake and release of molecular information, which is important in regulating cell behavior. In fact, many disease processes relate to disorganized cell-surface communication systems. ADAMs 1 belong to a large family of cell-surface proteins with over 30 members. The prototypical ADAM molecule is a transmembrane glycoprotein composed of several distinct domains, including a prodomain and a metalloprotease, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domain. ADAMs play important roles in cell adhesion, interacting with integrins and syndecans, and in the proteolysis of the ectodomains of cell-surface proteins,

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Structure and expression of the murine ADAM 15 gene and its splice variants, and difference of interaction between their cytoplasmic domains and Src family proteins

Cited by 14 publications

References 25 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

Characterisation of the Human ADAM15 Promoter

Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ϵ

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