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The Eph tyrosine kinase receptors EphB2 and EphA2 are novel proteolytic
substrates of tissue factor/coagulation factor VIIa
#MMPMID25281742
Eriksson O
; Ramström M
; Hörnaeus K
; Bergquist J
; Mokhtari D
; Siegbahn A
J Biol Chem
2014[Nov]; 289
(47
): 32379-91
PMID25281742
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Tissue factor (TF) binds the serine protease factor VIIa (FVIIa) to form a
proteolytically active complex that can trigger coagulation or activate cell
signaling. Here we addressed the involvement of tyrosine kinase receptors (RTKs)
in TF/FVIIa signaling by antibody array analysis and subsequently found that
EphB2 and EphA2 of the Eph RTK family were cleaved in their ectodomains by
TF/FVIIa. We used N-terminal Edman sequencing and LC-MS/MS analysis to
characterize the cleaved Eph isoforms and identified a key arginine residue at
the cleavage site, in agreement with the tryptic serine protease activity of
FVIIa. Protease-activated receptor 2 (PAR2) signaling and downstream coagulation
activity was non-essential in this context, in further support of a direct
cleavage by TF/FVIIa. EphB2 was cleaved by FVIIa concentrations in the
subnanomolar range in a number of TF expressing cell types, indicating that the
active cellular pool of TF was involved. FVIIa caused potentiation of cell
repulsion by the EphB2 ligand ephrin-B1, demonstrating a novel proteolytical
event to control Eph-mediated cell segregation. These results define Eph RTKs as
novel proteolytical targets of TF/FVIIa and provide new insights into how
TF/FVIIa regulates cellular functions independently of PAR2.
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