Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling

Abstract

Heparin‐binding epidermal growth factor (HB‐EGF) and betacellulin (BTC) are activating ligands for EGF receptor (EGFR/ErbB1) and ErbB4. To identify their physiological functions, we disrupted mouse HB‐EGF and BTC alleles by homologous recombination. Most HB‐EGF−/− mice died before weaning, and survivors had enlarged, dysfunctional hearts and reduced lifespans. Although BTC−/− mice were viable and fertile and displayed no overt defects, the lifespan of double null HB‐EGF−/−/BTC−/− mice was further reduced, apparently due to accelerated heart failure. HB‐EGF−/− newborns had enlarged and malformed semilunar and atrioventricular heart valves, and hypoplastic, poorly differentiated lungs. Defective cardiac valvulogenesis was the result of abnormal mesenchymal cell proliferation during remodeling, and was associated with dramatic increases in activated Smad1/5/8. Consistent with the phenotype, HB‐EGF transcripts were localized to endocardial cells lining the margins of wild‐type valves. Similarly defective valvulogenesis was observed in newborn mice lacking EGFR and tumor necrosis factor‐α converting enzyme (TACE). These results suggest that cardiac valvulogenesis is dependent on EGFR activation by TACE‐derived soluble HB‐EGF, and that EGFR signaling is required to regulate bone morphogenetic protein signaling in this context.

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…Finally, in a panel of xenografts across several indications, the most sensitive models had higher levels of pEGFR. The involvement of the EGFR pathway in the mechanism of action of MEDI3622 is consistent with genetic data indicating that the Adam17 knockout mouse phenotype bears resemblance to that of the EGFR and HBEGF knockout mice (3)(4)(5). Also noteworthy, however, was the clear potential of MEDI3622 to inhibit EGFR-independent pathways as evidenced by the 56% DTGI in the cetuximab resistant 505 PDX model.…”

“…The phenotype of Adam17 knockout mice (3), however, closely aligns with those of EGFR and HBEGF knockout mice implicating ADAM17 in the shedding of ligands that transduce signals through EGFR family receptor tyrosine kinases (4,5) and implying that it is the shed form of these ligands which are responsible for the majority of EGFR-driven signaling. Indeed, knockout of Adam17 in mouse embryo fibroblasts dramatically reduces the amount of shed EGFR ligands (amphiregulin, epiregulin, HBEGF, TGFa) as well as the major ligand for HER3 (heregulin; ref.…”

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

“…The EGF family GFs include EGF, transforming growth factor-a (TGF-a), HB-EGF, AR, betacellulin, epiregulin, neuregulin, and epigen (Massague´and Pandiella, 1993;Harris et al, 2003); all of these are shed from the cell surface (Peschon et al, 1998;Lee et al, 2003;Sahin et al, 2004). Increasing evidence suggests that shedding of EGF family GF precursors regulates the availability and bioactivity of these factors and is essential for the activation of the ErbB-signaling pathways Jackson et al, 2003;Lee et al, 2003;Yamazaki et al, 2003). Members of the ADAM family, particularly ADAM17, have been shown to play an essential but not sole role in the shedding of these factors (Merlos-Suarez et al, 2001;Sahin et al, 2004).…”

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

“…Notably, ADAM17-null mice [39,40] display the same aberrant eyelid, hair and whisker phenotypes as TGFα-null mice [41,42], the same altered cardiac valve development as HB-EGF knockout and cleavage-resistant HB-EGF knockin mice [30,43,44], and the diverse epithelial defects and perinatal lethality of EGFR-deficient mice [45][46][47]. Moreover, studies using single-, triple-and quadruple-gene knockout mice lacking ADAMs 9, 12, 15 and/or 17 indicate that only ADAM17 is responsible for the open eyelid and cardiac valve phenotypes of EGFR, TGFα and HB-EGF deficient mice [36].…”

“…And indeed, instead of forming a competent ductal tree that fills the entire mammary fat pad, AREG-deficient mice form what could be called an inadequate bush-a small mammary shrub of insufficient size to nourish pups [25]. Moreover, AREG is the only EGFR agonist that is absolutely required, since ductal outgrowth was only impaired in AREG-null mice, but not in mice lacking either EGF, TGFα, HB-EGF or BTC alone or in various combinations [25,30].…”