hb-egf, transactivation, and cardiac hypertrophy - ScienceDirect

4 downloads 0 Views 79KB Size Report
of membrane-anchored metalloprotease. Inhibitor of metalloprotease prevents activation of HB-EGF and attenuates hypertrophic response of cardiomyocytes by ...


REVIEW ARTICLE

HB-EGF, TRANSACTIVATION, AND CARDIAC HYPERTROPHY Seiji Takashima1, Masafumi Kitakaze2* 1

Department of Cardiovascular Medicine, Graduate School of Medicine and Health Care Center, Osaka University, and 2Cardiovascular Division of Medicine, National Cardiovascular Center of Japan, Suita, Osaka, Japan.

SUMMARY Transactivation of epidermal growth factor receptor (EGFR) family ligands by G protein coupled receptor (GPCR) agonist plays important roles in many physiologic activities. In the heart, heparin-binding EGF-like growth factor (HB-EGF), which is one of the EGF family ligands, is an indispensable molecule for cardiac cell metabolism. Membrane-anchored HB-EGF is released by GPCR agonist stimulation and moves signals leading to hypertrophy. Amelioration of this signal transduction by HB-EGF genome deletion causes severe heart dysfunction, indicating the important role of HB-EGF in the heart. Cleavage of HB-EGF was mediated by activation of membrane-anchored metalloprotease. Inhibitor of metalloprotease prevents activation of HB-EGF and attenuates hypertrophic response of cardiomyocytes by GPCR agonists such as angiotensin II or catecholamine. These data strongly suggest that HB-EGF is involved in cardiac development and metabolism. The physiologic and clinical roles of EGF family ligands in the heart are reviewed. [International Journal of Gerontology 2007; 1(1): 2–9] Key Words: cardiac hypertrophy, heart failure, HB-EGF, metalloprotease

Introduction Signal transduction mediated by tyrosine kinase growth factor receptor is one of the important pathways for cellular proliferation. Many oncogenes are included in this signal transduction, leading to the idea that inhibitors of these signaling molecules can be used for cancer therapy1. On the other hand, growth factor itself has not been applied to clinical medicine for a long time even though it has strong biologic activity. Growth factors have been thought to have deleterious effects for promoting tumor formation and proliferation for clinical use. However, these effects have recently been proven to be minimal because of the downregulation of its receptor, although several specific growth factors such as erythropoietin and granulocyte colony-stimulating

*Correspondence to: Dr Masafumi Kitakaze, Cardiovascular Division of Medicine, National Cardiovascular Center of Japan, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail: [email protected] Accepted: December 1, 2006

2

factor have started to be used clinically, and their effects were proved to be significant and remarkable2,3. Thinking of their specificity and strong effects, growth factors are expected to be used for further clinical applications. Neurons and cardiomyocytes are nonproliferative cells; however, these cells are known to require growth signals for their survival. In neurons, a substance called neurotrophin is reported to be essential for their survival4; however, in cardiomyocytes, it is unknown what signal is essential for their survival. Cardiomyocytes stop their proliferation soon after birth and their number does not change much throughout life5. This limited proliferation ability causes difficulty in repair of heart muscles after injuries such as ischemia-reperfusion injury. We need to investigate how the proliferation and growth of cardiomyocytes may be induced. Several investigators including ourselves suggest that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is the potential candidate for cell growth and wound healing. In this review, we summarize the function of HBEGF, which is one of the EGF family of growth factors,

International Journal of Gerontology | March 2007 | Vol 1 | No 1 © 2007 Elsevier.



HB-EGF, Transactivation, and Cardiac Hypertrophy

especially for the metabolism of cardiomyocytes and discuss the probability of the clinical application of HBEGF in heart failure.

HB-EGF and Signaling of ErbB Family Receptors EGF growth factor family molecules including HB-EGF have ErbB family as their receptors. The ErbB family of receptor tyrosine kinases (RTKs) has fundamental roles in development, proliferation, and differentiation of various organs6. There are 4 members of the RTK ErbB family, EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4. EGF family ligands bind to and activate their receptors by inducing the formation of either homodimers or heterodimers, resulting in autophosphorylation of specific tyrosine residues within the cytoplasmic domain. The phosphorylated tyrosine residues bind to the adapter proteins, which are instrumental in mediating downstream signaling pathways that determine the biologic activity of EGF growth factor family molecules. In vertebrates, the EGF family of ligands binds to ErbB receptors with some degree of preference. EGF, transforming growth factor-α (TGF-α), and amphiregulin bind to ErbB1; HB-EGF, epiregulin, and betacellulin bind to both ErbB1 and ErbB4; NRG-1 (neuregulin/heregulin/ NDF) and NRG-2 bind to ErbB3 and ErbB4; NRG-3 and NRG-4 bind to ErbB4 but not to ErbB3. Although no ligand for ErbB2 has yet been described, ErbB2 is active as a signaling receptor by forming heterodimers with other ErbB receptors7. HB-EGF is synthesized as a type I transmembrane protein (proHB-EGF) composed of signal peptide, heparinbinding, EGF-like, juxtamembrane, transmembrane, and cytoplasmic domains8,9. The membrane-bound proHB-EGF is cleaved at the juxtamembrane domain, resulting in the shedding of soluble HB-EGF10. A similar mechanism regulates other EGF family ligands and determines the specific role at their target site11–13. The full-length proHB-EGF is biologically active as a juxtacrine growth factor that transmits the signals to neighboring cells in a nondiffusible manner14–16. ProHB-EGF forms complexes with CD917 on the cell membrane. ProHB-EGF is also the receptor for diphtheria toxin (DT), and mediates the entry of DT into the cytoplasm18,19. Soluble HB-EGF is a potent mitogen and chemoattractant for a number of cell types including

International Journal of Gerontology | March 2007 | Vol 1 | No 1



vascular smooth muscle cells (VSMCs), fibroblasts, and keratinocytes20,21. HB-EGF has been implicated in many physiologic and pathologic processes, which include wound healing22,23, cardiac hypertrophy24, smooth muscle cell hyperplasia25, kidney collecting duct morphogenesis26, blastocyst implantation27, pulmonary hypertension28, and oncogenic transformation29. Gene-targeted mouse studies indicate that the ErbB RTKs are critical for normal heart development. ErbB1 null mice with a CD1 background, and ErbB1 mutant (waved-2) mice exhibit semilunar valve enlargement30. ErbB2 null mouse embryos die from a defect in trabeculae formation31. The phenotype of ErbB4 knockout mice is also embryonically lethal due to a similar abnormal trabeculae formation as are mice lacking NRG, the ErbB4 ligand32. Disruption of the ErbB3 gene causes heart valve malformation, whereas trabeculae formation is not affected33. The ErbB family is required also for the maintenance of normal heart function in the adult. Ventricle-specific conditional ErbB2 knockout mice have severe heart failure with dilated ventricles and decreased contractility function. These symptoms resemble human dilated cardiomyopathy34,35. These lines of evidence strongly suggest the tight relationship between EGF growth factor signal and cardiac development/metabolism.

HB-EGF and Cardiac Hypertrophy The important role of HB-EGF on cardiomyocytes was first disclosed by an accidental discovery during the screening of metalloprotease inhibitors for drugs to treat diabetic mice. One of the novel metalloprotease inhibitors called KBR-7785 strongly inhibited cardiac hypertrophy in vivo. KBR-7785 also inhibited cardiac hypertrophy done by aortic banding of mice24. These data suggested that metalloprotease activity is involved in cardiac hypertrophy. At the same time, Prenzel et al. reported that ErbB1 phosphorylation by endothelin was mediated by cleaved HB-EGF through membraneanchored metalloprotease in tumor cells36. In this report, metalloprotease inhibitor completely inhibited ErbB1 phosphorylation by G protein coupled receptor (GPCR) agonists such as endothelin or thrombin. They concluded that GPCR agonists activated cell membrane metalloprotease and cleaved HB-EGF and released HBEGF that binds to ErbB1. This ErbB1 phosphorylation by GPCR agonists is called transactivation because GPCR

3





S. Takashima, M. Kitakaze

agonists do not directly bind to ErbB1. The transactivation of EGFR by GPCR agonists was first reported in 199637. However, it was surprising that this transactivation was mediated by cleaved growth factor from cell membrane. Since GPCR agonists were also known to induce cardiac hypertrophy38, metalloprotease KBR7785 was thought to inhibit GPCR agonist-induced cardiac hypertrophy by preventing cleavage of HB-EGF. Substantial evidence indicates the existence of RTKs, including ErbB1, in the heart24,35,39,40. Using rat neonatal cardiomyocytes, EGFR phosphorylation by GPCR agonists was examined and it was observed that HB-EGF phosphorylates its receptor (ErbB1). At the same time, GPCR agonists phosphorylate ErbB1. This transactivation was completely blocked by the metalloprotease inhibitor KBR-7785 or neutralizing antibody for HB-EGF. Both KBR-7785 and the neutralizing antibody for HB-EGF also attenuated the hypertrophy of cardiomyocytes mediated by either aortic banding or GPCR agonists in vivo. These data suggest that GPCR agonists utilize HB-EGF-mediated transactivation as a common pathway for cardiac hypertrophy. Moreover, A disintegrin and metalloprotease (ADAM) 12 was identified as a major

metalloprotease for HB-EGF cleaving in cardiomyocytes24. This unique signaling mechanism is illustrated in Figure 1. In this model, once extracellular stimuli are incorporated into the cell, then the inside-out signal as growth factor shedding occurs. Shedded growth factor binds and activates EGFR from outside of the cell membrane. This inside-out signaling seems rather ineffective; however, this mechanism may be more plausible than the intracellular transactivation of EGFR by GPCR agonists. EGF ligands including HB-EGF bind to EGFR from outside the cell membrane, and dynamically change the conformation of EGFR, leading to the autophosphorylation of EGFR dimer41–43. Thinking of the necessity of complex conformation change, activation of EGFR without the ligand binding is rather unlikely. Instead, shedding of membrane-anchored ligand is a more likely mechanism of transactivation of EGFR after the stimulation of GPCR. GPCR agonist regulates rapid response of cell activity such as contractility mediated by transient change of intracellular signal such as calcium44. Growth signaling is a rather slow cellular response. EGFR transactivation may be a shearing mechanism to handle different cellular responses to GPCR agonists.

sHB-EGF

KBR-7785 HB-EGF Phe

Ang II

ET-1 EGF receptor

GPCR ADAM12

Cardiac hypertrophy Cardiomyocyte survival? Figure 1. G protein coupled receptor (GPCR) agonists activate membrane-anchored A disintegrin and metalloprotease (ADAM) 12, which is cleaved enzyme for membrane-anchored heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF). Cleaved HB-EGF binds and activates EGF receptor from outside of the cell membrane. Growth signal mediated by downstream signal such as ERK-1,2 induces cardiac hypertrophy. Metalloprotease inhibitor KBR-7785 inhibits ADAM12, resulting in unsuccessful cleaving of HB-EGF from cell membrane after GPCR ligand stimulation.

4

International Journal of Gerontology | March 2007 | Vol 1 | No 1



HB-EGF, Transactivation, and Cardiac Hypertrophy

ErbB Receptor Transactivation and Ectodomain Shedding of HB-EGF Indeed, many of the mitogenic effects of GPCR agonists are mediated through transactivation of EGFR. Besides the heart, the inhibition of EGFR kinase using the selective inhibitor AG1478 abolishes GPCR agonistmediated downstream signaling such as activation of ERK-1,2 in several cell types, including VSMCs and cardiac myocytes45,46, and growth and migration of VSMCs47. Thus, the transactivation of EGFRs by GPCRs explains the majority of growth-promoting responses. EGFR, an RTK, is endogenously expressed in numerous cell types and is an important factor in the control of many fundamental cellular processes, including cellular migration, metabolism, and survival, in addition to cellular proliferation and differentiation48. RTKs possess an extracellular ligand-binding domain connected to the cytoplasmic domain by a single transmembrane helix. The cytoplasmic domain contains a conserved protein kinase core and additional regulatory sequences that are subjected to autophosphorylation and phosphorylation by other protein kinases49. Overexpression of EGFR often results in uncontrolled growth and tissue remodeling. Not surprisingly, EGFR and its ligands are frequently upregulated in human cancers. Consequently, blocking the proliferative effects of EGFR activation has potential therapeutic applications in cancer and aberrant tissue growth. Then, a part of the effect of GPCR agonists might be mediated by EGFR kinase activated by truncated EGFR ligand family. Ectodomain shedding of proHB-EGF is induced by various stimuli including phorbol esters, calcium ionophore, and lysophosphatidic acid10,50,51. Multiple signaling cascades such as the mitogen-activated protein kinase and protein kinase C pathways appear to regulate HB-EGF shedding52,53. Metalloproteases were implicated as the protease for shedding of proHBEGF since various metalloprotease inhibitors inhibited ectodomain shedding of HB-EGF efficiently. Matrix metalloprotease (MMP) 3, MMP7, ADAM9, ADAM10, ADAM12, and ADAM17 have been implicated as responsible proteases24,53–57. The specific proteases involved in the shedding process of HB-EGF depend on cell type and biologic environment. For example, MMP7 appears to be involved in the shedding process in epithelial cells, especially on the apical surface of cells. On the other hand, ADAM12 seems to be responsible for HBEGF shedding in cardiomyocytes. Pro148-Val149 and

International Journal of Gerontology | March 2007 | Vol 1 | No 1



Glu151-Asn152 have been suggested as the shedding sites of proHB-EGF54. Highly specific HB-EGF shedding inhibitors have been found by a screening of hydroxamic acid-based compounds. They inhibit cutaneous wound healing and cardiac hypertrophy in mice and submandibular gland development in organ culture, suggesting that ectodomain shedding of HB-EGF is essential for various pathophysiologic processes and that its inhibition might be a novel therapeutic strategy23,24.

Cardiac Phenotype of HB-EGF Gene-targeting Mouse To further clarify the in vivo role of HB-EGF in cardiac metabolism, a gene-targeting mouse of HB-EGF was established. One of the HB-EGF gene aberrant mice was designed to make a mouse in which HB-EGF was not cleaved from cell membrane (HB-EGFuc/uc)58. An uncleavable form of proHB-EGF was generated by creating double point mutations in the juxtamembrane domain. HB-UC (a product of HBuc) was also resistant to ectodomain shedding in response to various sheddinginducing stimuli, while the other biologic properties of HB-UC were similar to those of WT proHB-EGF. To assess the biologic significance of proHB-EGF ectodomain shedding, mutant mice expressing HB-UC instead of WT proHB-EGF were also generated by targeted replacement of the proHB-EGF gene with HBuc complementary deoxyribonucleic acid. Homozygous mice (HBuc/uc) were born at the predicted Mendelian frequency. Northern blotting of the transcripts obtained from adult mice indicated that the WT and HBuc alleles were expressed equally in the heart, lung, and kidney. Uncleavability of HB-EGF was also confirmed in vivo. HB-EGFuc/uc has a relatively short life and showed remarkable cardiac specific phenotype even though HB-EGF was replaced by an uncleavable form in the whole body. At 12 weeks, the hearts of HB-EGFpro/ pro mice were dilated and showed diminished movement. Histologically, the cardiomyocytes of HB-EGFuc/uc mice were degraded and replaced with fibrosis. Echocardiography showed that the ejection fraction of HB-EGFuc/uc mice was severely diminished. These phenotypic changes are quite similar to human dilated cardiomyopathy. HB-EGF null mice (HB-EGFdel/del) were also produced by gene targeting and they showed similar heart failure59. As with HB-EGFuc/uc mice, HB-EGF null mice

5



S. Takashima, M. Kitakaze

showed obvious phenotype only in the heart, even though HB-EGF was absent in the whole body. Although studies of HBuc/uc mice indicated that ectodomain shedding of proHB-EGF and release of sHB-EGF are necessary for proper HB-EGF function in vivo, the physiologic importance of the control of proHB-EGF ectodomain shedding remains unclear. To address this issue, another mouse mutant that only expresses sHB-EGF was designed. The transmembrane domain-truncated mutant (HB tm) was generated by insertion of a stop codon in the major site for proHB-EGF processing. Mitogenic activity was similar between HB-TM (product of HB tm) and WT sHB-EGF derived from proHB-EGF shedding, but HB-TM is secreted at much higher levels than WT sHB-EGF. The targeting construct for HB tm is similar to that for HBuc. One allele of the proHB-EGF gene in embryo stem (ES) cells was replaced with HB tm through homologous recombination. Chimeric mice carrying HB tm were generated from these ES clones. Most chimeric founders exhibited abnormally small bodies and thickened skin. Morphologic abnormalities were also found in the heart of HB tm mice. Histologic specimens showed ventricular hypertrophy in hearts from HB tm E16.5 embryos. The cardiac muscle fibers in chimeric mice were loose, with enlarged nuclei. These results suggest that the expression of HB tm reduces cardiomyocyte differentiation or terminates proliferation. These cardiac developmental abnormalities may be the primary cause of early death in HB tm mice. The phenotype observed in HB tm mice is likely due to deregulated secretion of sHBEGF. Under normal conditions, a portion of proHB-EGF molecules is converted to sHB-EGF, but the majority of proHB-EGF molecules on the cell surface seem to be internalized without shedding10. In the case of HB tm, most synthesized molecules would be secreted without shedding, resulting in oversecretion of sHB-EGF even though the native HB-EGF promoter regulates gene expression. Therefore, deregulated secretion of sHB-EGF would result in severe cardiac hypertrophy. The present study thus confirms the notion that ectodomain shedding of proHB-EGF must be strictly controlled in vivo. Also, HB-EGF is an important growth regulator of cardiomyocytes. HB-EGF and its cleavage from cell membranes are important not only for cardiac hypertrophy by GPCR agonists but also fundamental metabolism for cardiomyocytes. HB-EGF might have the role of a survival factor, like neurotrophin in neurons, by exerting growth signal in cardiomyocytes.

6



EGFR in Cardiomyocytes and HB-EGF Transactivation of ErbB1 by GPCR agonists was stated above; however, there are 4 different subtypes of EGFRs that exist genetically. To understand the precise physiologic roles of HB-EGF, it is essential to examine which receptor subtypes are used in cardiomyocytes. Binding affinity and capacity for phosphorylation of EGFRs are different for each EGF family growth factor such as EGF and TGF-α. HB-EGF can bind to ErbB1, 3, and 4 and phosphorylates ErbB1, 2, and 3. ErbB4 is weakly phosphorylated by HB-EGF60. Since ErbB3 is rarely expressed in cardiomyocytes, cardiac function mediated by HB-EGF is mainly mediated by ErbB1, 2, and 4. Indeed gene-targeting ErbB2 null mice showed the severe cardiac phenotype35, suggesting that HB-EGF signal is partly mediated by ErbB2. Since ErbB2 does not have physiologic ligands, ErbB2 forms heterodimer with ErbB1 or 4. Therefore, ErbB2 is phosphorylated by binding of EGF family growth factor to ErbB1 or 4. In cardiomyocytes, HB-EGF can enhance the phosphorylation of ErbB1, 2, and 4. The in vivo phosphorylation of HB-EGF null mice (HB-EGFdel/del) heart showed that endogenous ErbB2 and 4 phosphorylation is attenuated. We are now generating mice expressing receptorspecific ligands in cardiomyocytes to rescue HB-EGF null mice to clarify which EGFRs are important for cardiac metabolism.

Future Clinical Application of HB-EGF There is clinical evidence implying the important role of HB-EGF in cardiac metabolism. Humanized antibody against ErbB2 (trastuzumab) is clinically used for the treatment of advanced breast cancer all over the world. In an early clinical trial, the combined therapy of trastuzumab with anthracycline worsened heart function in 28% of patients61. Trastuzumab possibly enhanced the cardiac toxicity of anthracycline. Since ErbB2 is an important signaling molecule for HBEGF, blocking of ErbB2 signal by trastuzumab might cause the impairment of HB-EGF signal, resulting in the enhancement of cardiac toxicity. Anthracycline is reported to induce cardiac toxicity by oxiradical. Cardiomyocytes damaged by this oxiradical might require more HB-EGF to maintain functional metabolism. ErbB2 antibody trastuzumab is now prohibited for combined use with anthracycline. In such cases, HB-EGF

International Journal of Gerontology | March 2007 | Vol 1 | No 1



HB-EGF, Transactivation, and Cardiac Hypertrophy

administration could improve the cell damage. Also, in case of other damage of cardiomyocytes such as ischemia or myocarditis, HB-EGF could help in the recovery of surviving cardiomyocytes. Growth factor therapy still has some difficult aspects, especially concerning tumor progression; however, its beneficial effect to tissue is potent. Clinical trials using growth hormone or insulin-like growth factor for heart failure is already in progress62,63. We are still examining the biochemical property of EGF signaling using HB-EGF-targeting mice, seeking the possibility of growth factor therapy for heart failure.

9.

10.

11.

12.

Acknowledgments This study was supported by Grants on Human Genome, Tissue Engineering and Food Biotechnology (H13Genome-11) and Grants on Comprehensive Research on Aging and Health (H13-21seiki(seikatsu)-23), in Health and Labor Sciences Research from the Ministry of Health, Labor, and Welfare, Japan.

13.

14.

References 1.

2.

3. 4.

5. 6.

7.

8.

Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Natl Rev Cancer 2005; 5: 341–54. Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288: 2827–35. Antman KH. G-CSF and GM-CSF in clinical trials. Yale J Biol Med 1990; 63: 387–410. Kalb R. The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci 2005; 28: 5–11. Pasumarthi KB, Field LJ. Cardiomyocyte cell cycle regulation. Circ Res 2002; 90: 1044–54. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19: 3159–67. Tzahar E, Yarden Y. The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands. Biochim Biophys Acta 1998; 1377: M25–37. Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem 1992; 267: 6205–12.

International Journal of Gerontology | March 2007 | Vol 1 | No 1

15.

16.

17.

18.

19.



Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 1991; 251: 936–9. Goishi K, Higashiyama S, Klagsbrun M, Nakano N, Umata T, Ishikawa M, et al. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell 1995; 6: 967–80. Fan H, Derynck R. Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J 1999; 18: 6962–72. Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17dependent shedding of epithelial amphiregulin. Development 2005; 132: 3923–33. Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factoralpha-converting enzyme. Mol Cell Neurosci 2000; 16: 631–48. Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M, et al. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol 1995; 128: 929–38. Iwamoto R, Mekada E. Heparin-binding EGF-like growth factor: a juxtacrine growth factor. Cytokine Growth Factor Rev 2000; 11: 335–44. Iwamoto R, Handa K, Mekada E. Contact-dependent growth inhibition and apoptosis of epidermal growth factor (EGF) receptor-expressing cells by the membraneanchored form of heparin-binding EGF-like growth factor. J Biol Chem 1999; 274: 25906–12. Mitamura T, Iwamoto R, Umata T, Yomo T, Urabe I, Tsuneoka M, et al. The 27-kD diphtheria toxin receptorassociated protein (DRAP27) from vero cells is the monkey homologue of human CD9 antigen: expression of DRAP27 elevates the number of diphtheria toxin receptors on toxin-sensitive cells. J Cell Biol 1992; 118: 1389–99. Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J 1994; 13: 2322–30. Naglich JG, Metherall JE, Russell DW, Eidels L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 1992; 69: 1051–61.

7



S. Takashima, M. Kitakaze

20. Higashiyama S, Abraham JA, Klagsbrun M. Heparinbinding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol 1993; 122: 933–40. 21. Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta 1997; 1333: F179–99. 22. Marikovsky M, Breuing K, Liu PY, Eriksson E, Higashiyama S, Farber P, et al. Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc Natl Acad Sci USA 1993; 90: 3889–93. 23. Tokumaru S, Higashiyama S, Endo T, Nakagawa T, Miyagawa JI, Yamamori K, et al. Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. J Cell Biol 2000; 151: 209–20. 24. Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med 2002; 8: 35–40. 25. Miyagawa J, Higashiyama S, Kawata S, Inui Y, Tamura S, Yamamoto K, et al. Localization of heparin-binding EGF-like growth factor in the smooth muscle cells and macrophages of human atherosclerotic plaques. J Clin Invest 1995; 95: 404–11. 26. Takemura T, Hino S, Kuwajima H, Yanagida H, Okada M, Nagata M, et al. Induction of collecting duct morphogenesis in vitro by heparin-binding epidermal growth factor-like growth factor. J Am Soc Nephrol 2001; 12: 964–72. 27. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, et al. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development 1994; 120: 1071–83. 28. Lemjabbar H, Basbaum C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med 2002; 8: 41–6. 29. Fu S, Bottoli I, Goller M, Vogt PK. Heparin-binding epidermal growth factor-like growth factor, a v-Jun target gene, induces oncogenic transformation. Proc Natl Acad Sci USA 1999; 96: 5716–21. 30. Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, Green PJ, et al. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 2000; 24: 296–9. 31. Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378: 394–8. 32. Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature 1995; 378: 386–90.

8



33. Erickson SL, O’Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M, et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2and heregulin-deficient mice. Development 1997; 124: 4999–5011. 34. Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 2002; 99: 8880–5. 35. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–65. 36. Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 1999; 402: 884–8. 37. Daub H, Weiss FU, Wallasch C, Ullrich A. Role of transactivation of the EGF receptor in signaling by G-proteincoupled receptors. Nature 1996; 379: 557–60. 38. Adams JW, Brown JH. G-proteins in growth and apoptosis: lessons from the heart. Oncogene 2001; 20: 1626–34. 39. Kudoh S, Komuro I, Hiroi Y, Zou Y, Harada K, Sugaya T, et al. Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J Biol Chem 1998; 273: 24037–43. 40. Thomas WG, Brandenburger Y, Autelitano DJ, Pham T, Qian H, Hannan RD. Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. Circ Res 2002; 90: 135–42. 41. Fickova M. Structure and activation of EGF receptor: minireview. Endocr Regul 2002; 36: 87–93. 42. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Jr, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003; 421: 756–60. 43. Cho HS, Leahy DJ. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002; 297: 1330–3. 44. Perez DM, Karnik SS. Multiple signaling states of G-protein-coupled receptors. Pharmacol Rev 2005; 57: 147–61. 45. Eguchi S, Inagami T. Signal transduction of angiotensin II type 1 receptor through receptor tyrosine kinase. Regul Pept 2000; 91: 13–20. 46. Kim S, Iwao H. Activation of mitogen-activated protein kinases in cardiovascular hypertrophy and remodeling. Jpn J Pharmacol 1999; 80: 97–102. 47. Saito S, Frank GD, Motley ED, Dempsey PJ, Utsunomiya H, Inagami T, et al. Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation. Biochem Biophys Res Commun 2002; 294: 1023–9.

International Journal of Gerontology | March 2007 | Vol 1 | No 1



HB-EGF, Transactivation, and Cardiac Hypertrophy

48. Zwick E, Bange J, Ullrich A. Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol Med 2002; 8: 17–23. 49. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 2002; 110: 669–72. 50. Dethlefsen SM, Raab G, Moses MA, Adam RM, Klagsbrun M, Freeman MR. Extracellular calcium influx stimulates metalloproteinase cleavage and secretion of heparinbinding EGF-like growth factor independently of protein kinase C. J Cell Biochem 1998; 69: 143–53. 51. Hirata M, Umata T, Takahashi T, Ohnuma M, Miura Y, Iwamoto R, et al. Identification of serum factor inducing ectodomain shedding of proHB-EGF and studies of noncleavable mutants of proHB-EGF. Biochem Biophys Res Commun 2001; 283: 915–22. 52. Gechtman Z, Alonso JL, Raab G, Ingber DE, Klagsbrun M. The shedding of membrane-anchored heparin-binding epidermal-like growth factor is regulated by the Raf/ mitogen-activated protein kinase cascade and by cell adhesion and spreading. J Biol Chem 1999; 274: 28828–35. 53. Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, et al. A metalloprotease-disintegrin, MDC9/ meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membraneanchored heparin-binding EGF-like growth factor. EMBO J 1998; 17: 7260–72. 54. Suzuki M, Raab G, Moses MA, Fernandez CA, Klagsbrun M. Matrix metalloproteinase-3 releases active heparinbinding EGF-like growth factor by cleavage at a specific juxtamembrane site. J Biol Chem 1997; 272: 31730–7. 55. Sunnarborg SW, Hinkle CL, Stevenson M, Russell WE, Raska CS, Peschon JJ, et al. Tumor necrosis factor-alpha

International Journal of Gerontology | March 2007 | Vol 1 | No 1

56.

57.

58.

59.

60.

61.

62.

63.



converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 2002; 277: 12838–45. Yan Y, Shirakabe K, Werb Z. The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J Cell Biol 2002; 158: 221–6. Yu WH, Woessner JF, Jr, McNeish JD, Stamenkovic I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 2002; 16: 307–23. Yamazaki S, Iwamoto R, Saeki K, Asakura M, Takashima S, Yamazaki A, et al. Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities. J Cell Biol 2003; 163: 469–75. Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci USA 2003; 100: 3221–6. Beerli RR, Hynes NE. Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 1996; 271: 6071–6. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer: anticancer therapy versus cardiotoxicity. Circulation 2000; 102: 272–4. Cittadini A, Isgaard J, Monti MG, Casaburi C, Di Gianni A, Serpico R, et al. Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol 2003; 41: 2154–63. Dreifuss P. Congestive heart failure and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) system. Am J Cardiol 2003; 92: 245–6.

9