PKCa and PKCd regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways
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PKCa and PKCd regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways. / Kveiborg, Marie; Instrell, Rachael; Rowlands, Christina; Howell, Michael; Parker, Peter J.
I: P L o S One, Bind 6, Nr. 2, 2011, s. e17168.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - PKCa and PKCd regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways
AU - Kveiborg, Marie
AU - Instrell, Rachael
AU - Rowlands, Christina
AU - Howell, Michael
AU - Parker, Peter J
PY - 2011
Y1 - 2011
N2 - Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCa as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCd and ERK activity. While PKCa specifically regulated PMA-induced shedding, PKCd and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction.
AB - Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCa as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCd and ERK activity. While PKCa specifically regulated PMA-induced shedding, PKCd and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction.
U2 - 10.1371/journal.pone.0017168
DO - 10.1371/journal.pone.0017168
M3 - Journal article
C2 - 21386996
VL - 6
SP - e17168
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 2
ER -
ID: 33823463