ADAM 17 is an enzyme that activates EGFR signaling by releasing EGFR ligands from the cell surface. Previous research showed that EGFR activation is required for skin tumor formation driven by the MET oncogene. This study found that ADAM 17 is necessary for EGFR activation by both MET and RAS oncogenes in keratinocytes. The researchers determined that MET activates a Src/iRhom pathway to upregulate ADAM 17 expression. Inhibition of Src, iRhom1 or iRhom2 reduced ADAM 17 activity in keratinocytes treated with HGF, linking MET to ADAM 17 through this pathway. Therefore, ADAM 17 appears to be a central player in producing the EGFR
1. ADAM 17: a common effector for RAS and MET-driven transformation of
primary keratinocytes
Mary Klosterman, Christophe Cataisson, Kelly Shibuya, Glenn Merlino and S.H.
Yuspa
ADAM 17 (a disintegrin and metalloproteinase 17) is considered an essential
membrane-anchored sheddase as it controls the signaling pathway of epidermal
growth factor receptor (EGFR) by liberating EGFR ligands from the cell surface.
Our previous data indicate that EGFR is an obligatory effector of MET driven
skin carcinogenesis. MET activates EGFR through enhanced transcriptional
expression and maturation of EGFR ligands by ADAM 17, thus establishing the
autocrine loops necessary for tumor formation. Transgenic keratinocyte
populations overexpressing HGF (MT-HGF) toactivate MET and keratinocytes
transduced with an oncogenic RAS share identical phenotypic and biochemical
features and produce tumors in vivo. EGFR activation by both MET and RAS
requires the activity of ADAM17 but the ability of various signaling pathways to
mediate ADAM17 activity remains to be understood. Here we use genetic and cell
biological approaches to determine potential MET effectors regulating ADAM17.
Recent studies have shown that Src and catalytically inactive members of the
rhomboid protease family, iRhom 1 and iRhom 2, are involved in the maturation
of ADAM17. By genetic deletion or siRNA mediated knock-down of ADAM 17, we
demonstrate that EGFR transactivation decreases in both RAS and MT-HGF
keratinocytes and reverses the gene signature associated with transformation.
When using release of the EGFR ligand amphiregulin (AREG) as readout for
ADAM17 activity, inhibition of Src, iRhom 1 and 2 reduce AREG release in culture
supernatants of HGF treated keratinocytes. Therefore, it appears that activation
of MET sets in motion a Src/iRhom mediated pathway toupregulate ADAM17.
These findings suggest that ADAM17 is a central player in producing the EGFR
activation critical for the oncogenic signature in both RAS and HGF/MET
transformed keratinocytes, further linking these two tumor initiators.
Understanding the critical downstream effectors of Adam 17 could lead to their
targeting for therapeutic purposes.