Regulation of TACE-dependent TGF-alpha shedding

The ErbB signaling network regulates many critical biological processes. This network consists of Epidermal Growth Factor Receptor (EGFR) and three related receptors and a superfamily of growth factor ligands. Signaling is initiated when EGF-like polypeptide ligands bind to EGFR, ErbB3 or ErbB4, causing receptor homo- or heterodimerization between the four related receptor tyrosine kinases, including the orphan receptor ErbB2. The EGF-like family of growth factors include: epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), heparin binding-epidermal growth factor (HB-EGF) betacellulin (BTC), epiregulin (EPR), epigen (EPI). The growth factors binding to ErbB receptors are produced as membrane anchored precursors that can be proteolytically cleaved in the extracellular juxtamembrane domain to release mature, soluble ligands, in a process termed ectodomain shedding. Metalloproteases, in particular the family of disintegrin and metalloproteases (ADAMs) have been identified as the proteases responsible for the shedding of diverse cell surface proteins. Efforts to understand the regulation of growth factor shedding led to the discovery of ADAM17, or tumor necrosis factor-alpha converting enzyme (TACE), as the major sheddase for the ErbB ligands. Evidence came from biochemical and in vivo studies, including mice lacking functional TACE due to a deletion in the metalloprotease domain. Homozygous TACE-deficient animals displayed perinatal lethality similar to EGFR-null mice and revealed subtle phenotypes that mimicked single growth factor null mice such as delayed eyelid closure like TGF-alpha deficient mice, heart and lung defects seen in the absence of HB-EGF and mammary gland development issues found in AR null creatures. Despite the recognition of a key role for TACE in development, understanding of the regulation mechanisms are incomplete. Several findings point to a role for MAPK pathways, non-receptor tyrosine kinases, calcium and calcium-dependent kinases and reactive oxygen species. The work described here identifies a pathway initiated by ATP binding to the P2Y family of GPCRs that mediates TACE-dependent TGF-alpha shedding and concomitant EGFR activation. Transactivation offers a physiologically relevant pathway to examine the mechanism of TACE regulation, which I use to identify mitochondria as a source of the key signaling intermediate in TACE activation, reactive oxygen species.