Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life

ABSTRACT MDC9 (ADAM9/meltrin γ) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an α secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9 −/− mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9 −/− mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9 −/− and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP α and γ secretase cleavage product (p3) and of β- and γ-secretase cleavage product (Aβ) in cultured hippocampal neurons from mdc9 −/− or wild-type mice, arguing against an essential major role of MDC9 as an α-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.

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Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor

Molecular Endocrinology ◽

10.1210/me.2003-0476 ◽

2004 ◽

Vol 18 (8) ◽

pp. 2035-2048 ◽

Cited By ~ 62

Author(s):

Bukhtiar H. Shah ◽

Akin Yesilkaya ◽

J. Alberto Olivares-Reyes ◽

Hung-Dar Chen ◽

László Hunyady ◽

...

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Types ◽

Specific Cell ◽

Heparin Binding ◽

Epidermal Growth

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Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor and CD9 on macrophages

Biochemical Journal ◽

10.1042/bj3280923 ◽

1997 ◽

Vol 328 (3) ◽

pp. 923-928 ◽

Cited By ~ 22

Author(s):

Noriyuki OUCHI ◽

Shinji KIHARA ◽

Shizuya YAMASHITA ◽

Shigeki HIGASHIYAMA ◽

Tsutomu NAKAGAWA ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Surface Marker ◽

Heparin Binding ◽

Atherosclerotic Lesions ◽

Growth Activity ◽

Epidermal Growth ◽

Egf Family ◽

Formalin Fixed

Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have previously determined that HB-EGF is expressed in macrophages and SMCs of human atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are expressed on macrophages, they may strongly promote the development of atherosclerosis. In the present study we have investigated the changes in proHB-EGF and CD9 in THP-1 cells during differentiation into macrophages and by the addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at both the mRNA and the protein level were up-regulated after differentiation into macrophages, and further expression of HB-EGF was induced by the addition of OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth was suppressed to control levels by an inhibitor of HB-EGF and was partially decreased by anti-CD9 antibodies. These results suggest that co-expression of proHB-EGF and CD9 on macrophages plays an important role in the development of atherosclerosis by a juxtacrine mechanism.

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A Tale of Two Cbls: Interplay of c-Cbl and Cbl-b in Epidermal Growth Factor Receptor Downregulation

Molecular and Cellular Biology ◽

10.1128/mcb.01809-07 ◽

2008 ◽

Vol 28 (9) ◽

pp. 3020-3037 ◽

Cited By ~ 51

Author(s):

Steven Pennock ◽

Zhixiang Wang

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Egf Receptor ◽

Growth Factor Receptor ◽

Wild Type ◽

Receptor Downregulation ◽

Epidermal Growth ◽

Precise Role ◽

Second Peak

ABSTRACT The precise role of Cbl in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking remains to be fully uncovered. Here, we showed that mutant EGFR1044, which was truncated after residue 1044, did not associate with c-Cbl and was not ubiquitinated initially in response to EGF but was internalized with kinetics similar to those of wild-type EGFR. This finding indicates that c-Cbl-mediated ubiquitination is not required for EGF-induced EGFR endocytosis. We also showed that the previously identified internalization-deficient mutant receptor EGFR1010LL/AA bound to c-Cbl and was fully ubiquitinated in response to EGF, which indicates that c-Cbl binding and ubiquitination are not sufficient for EGFR internalization. We next investigated EGFR trafficking following EGFR internalization. We found that c-Cbl disassociation from EGFR occurred well in advance of EGFR degradation and that this event was concurrent with the selective dephosphorylation of EGFR at Y1045. This finding suggests that once EGFR is ubiquitinated, continual Cbl association is not required for EGFR degradation. Because EGFR1044 is ubiquitinated and degraded similarly to wild-type EGFR, we examined the role of another prominent Cbl homologue, Cbl-b, and found that Cbl-b was associated with both EGFR and EGFR1044. Further study showed that Cbl-b bound to EGFR at two regions: one in the C-terminal direction from residue 1044 and one in the N-terminal direction from residue 958. Moreover, Cbl-b association with EGFR rose markedly following a decrease in c-Cbl association, corresponding to a second peak of EGFR ubiquitination occurring later in EGFR trafficking. Using RNA interference to knock down both c-Cbl and Cbl-b, we were able to abolish EGFR downregulation. This knockdown had no affect on the rate of EGF-induced EGFR internalization. We found that the two Cbls accounted for total receptor ubiquitination and that while c-Cbl and Cbl-b are each alone sufficient to effect EGFR degradation, both are involved in the physiological, EGF-mediated process of receptor downregulation. Furthermore, these data ultimately reveal a previously unacknowledged temporal interplay of two major Cbl homologues with the trafficking of EGFR.

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Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.12-11236 ◽

2013 ◽

Vol 54 (6) ◽

pp. 3815 ◽

Cited By ~ 7

Author(s):

Yuki Inoue ◽

Kazuhiro Tsuruma ◽

Tomohiro Nakanishi ◽

Atsushi Oyagi ◽

Yuta Ohno ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Mouse Retina ◽

Heparin Binding ◽

Photoreceptor Degeneration ◽

Epidermal Growth

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Role of heparin-binding epidermal growth factor–like growth factor as a hepatotrophic factor in rat liver regeneration after partial hepatectomy

Hepatology ◽

10.1002/hep.1840220535 ◽

1995 ◽

Vol 22 (5) ◽

pp. 1584-1590 ◽

Cited By ~ 1

Author(s):

Shinichi Kiso ◽

Sumio Kawata ◽

Shinji Tamura ◽

Shigeki Higashiyama ◽

Nobuyuki Ito ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Rat Liver ◽

Heparin Binding ◽

Rat Liver Regeneration ◽

Epidermal Growth

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Possible pro-inflammatory role of heparin-binding epidermal growth factor-like growth factor in the active phase of systemic sclerosis

The Journal of Dermatology ◽

10.1111/1346-8138.14088 ◽

2017 ◽

Vol 45 (2) ◽

pp. 182-188

Author(s):

Megumi Hirabayashi ◽

Yoshihide Asano ◽

Takashi Yamashita ◽

Shunsuke Miura ◽

Kouki Nakamura ◽

...

Keyword(s):

Systemic Sclerosis ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Active Phase ◽

Heparin Binding ◽

Epidermal Growth

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Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching

Kidney International ◽

10.1046/j.1523-1755.2002.00358.x ◽

2002 ◽

Vol 61 (6) ◽

pp. 1968-1979 ◽

Cited By ~ 21

Author(s):

Tsukasa Takemura ◽

Satoshi Hino ◽

Mituru Okada ◽

Yuka Murata ◽

Hidehiko Yanagida ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cell ◽

Epidermal Growth Factor ◽

Heparin Binding ◽

Renal Epithelial Cell ◽

Epidermal Growth ◽

Membrane Bound

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Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF

The Journal of Cell Biology ◽

10.1083/jcb.200303017 ◽

2003 ◽

Vol 163 (3) ◽

pp. 489-502 ◽

Cited By ~ 107

Author(s):

Daisuke Nanba ◽

Akiko Mammoto ◽

Koji Hashimoto ◽

Shigeki Higashiyama

Keyword(s):

Growth Factor ◽

Nuclear Export ◽

Cell Cycle Progression ◽

Growth Factor Receptor ◽

Heparin Binding ◽

Epidermal Growth ◽

Carboxy Terminal ◽

G Protein Coupled ◽

In Cells

Cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) via metalloprotease activation yields amino- and carboxy-terminal regions (HB-EGF and HB-EGF-C, respectively), with HB-EGF widely recognized as a key element of epidermal growth factor receptor transactivation in G protein–coupled receptor signaling. Here, we show a biological role of HB-EGF-C in cells. Subsequent to proteolytic cleavage of proHB-EGF, HB-EGF-C translocated from the plasma membrane into the nucleus. This translocation triggered nuclear export of the transcriptional repressor, promyelocytic leukemia zinc finger (PLZF), which we identify as an HB-EGF-C binding protein. Suppression of cyclin A and delayed entry of S-phase in cells expressing PLZF were reversed by the production of HB-EGF-C. These results indicate that released HB-EGF-C functions as an intracellular signal and coordinates cell cycle progression with HB-EGF.

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Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions

Development ◽

10.1242/dev.117.3.1113 ◽

1993 ◽

Vol 117 (3) ◽

pp. 1113-1123 ◽

Cited By ~ 31

Author(s):

P. Heitzler ◽

P. Simpson

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Fate ◽

Cell Interactions ◽

Signalling Pathway ◽

Neural Precursor ◽

Wild Type ◽

Cell Fate Decisions ◽

Epidermal Growth

In Drosophila each neural precursor is chosen from a group of cells through cell interactions mediated by Notch and Delta which may function as receptor and ligand (signal), respectively, in a lateral signalling pathway. The cells of a group are equipotential and express both Notch and Delta. Hyperactive mutant Notch molecules, (Abruptex), probably have an enhanced affinity for the ligand. When adjacent to wild-type cells, cells bearing the Abruptex proteins are unable to produce the signal. It is suggested that in addition to the binding of Notch molecules on one cell to the Delta molecules of opposing cells, the Notch and Delta proteins on the surface of the same cell may interact. Binding between a cell's own Notch and Delta molecules would alter the availability of these proteins to interact with their counterparts on adjacent cells.

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