Extracellular Signal-regulated Kinase Phosphorylates Tumor Necrosis Factor α-converting Enzyme at Threonine 735: A Potential Role in Regulated Shedding

Abstract

The ectodomain of certain transmembrane proteins can be released by the action of cell surface proteases, termed secretases. Here we have investigated how mitogen-activated protein kinases (MAPKs) control the shedding of membrane proteins. We show that extracellular signal-regulated kinase (Erk) acts as an intermediate in protein kinase C-regulated TrkA cleavage. We report that the cytosolic tail of the tumor necrosis factor ␣-converting enzyme (TACE) is phosphorylated by Erk at threonine 735. In addition, we show that Erk and TACE associate. This association is favored by Erk activation and by the presence of threonine 735. In contrast to the Erk route, the p38 MAPK was able to stimulate TrkA cleavage in cells devoid of TACE activity, indicating that other proteases are also involved in TrkA shedding. These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by MAPKs may regulate the proteolytic function of membrane secretases.

TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNFα in LPS-stimulated macrophages

“…It is therefore possible that a covalent modification of TACE, such as phosphorylation, is required for the ERK1/2-stimulated cell surface expression and processing of pre-TNF␣. A further reason for considering this possibility was that phorbol esters and growth factors have been shown to stimulate the phosphorylation of wild-type TACE, as well as TACE-dependent shedding of the TRKA (NTRK1) receptor (Diaz-Rodriguez et al, 2002). Moreover, the phorbol-ester-induced shedding of the TRKA receptor is suppressed by the MKK1 inhibitor U0126 (Diaz-Rodriguez et al, 2002; Soond et al, 2005), and the phorbol ester-stimulated phosphorylation of TACE did not occur if Thr735 was mutated to Ala.…”

Acute Alcohol Inhibits TNF-α Processing in Human Monocytes by Inhibiting TNF/TNF-α-Converting Enzyme Interactions in the Cell Membrane

“…The mechanism of this reduction in interaction at present is unclear. Possibilities include changes in membrane fluidity (33) induced by EtOH (33), alterations in raft compartments, or perhaps abnormal ERK-mediated phosphorylation of TACE, which is critical for protein kinase Cregulated TrkA cleavage (34). Although there are no specific studies of yet examining TNF/TACE interactions in the context of membrane rafts, members of the TNF receptor superfamily, CD40 and CD120a (35,36), as well as ␣ secretases (37) have been localized to membrane rafts.…”

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

“…We investigated whether the intracellular domain of ADAM17 plays a role in S1P-induced breast CSC proliferation. ADAM17 activity is regulated by phosphorylation-dependent mechanisms [29][30][31] ; therefore, we generated ADAM17 mutants with either Thr735 (p38MAPK consensus motif) or Thr761 (Akt consensus motif) replaced by alanine (Fig. 4a).…”