Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:4.2.2.7 (
heparinase
)
1,270
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The activities of insulin-like growth factor (IGF)-I and -II are regulated by IGF-binding proteins (IGFBPs). Cleavage of IGFBP-4 by the metalloproteinase
pregnancy-associated plasma protein-A
(
PAPP-A
) causes release of bound IGF and has been established in several biological systems including the human reproductive system. Using flow cytometry, we first demonstrate that
PAPP-A
reversibly binds to the cell surface of several cell types analyzed. Heparin and heparan sulfate, but not dermatan or chondroitin sulfate, effectively compete for
PAPP-A
surface binding, and because incubation of cells with
heparinase
abrogated
PAPP-A
adhesion, binding is probably mediated by a cell surface heparan sulfate proteoglycan. Furthermore, the proteolytic activity of
PAPP-A
is preserved while bound to cells, suggesting that adhesion functions to target its activity to the vicinity of the IGF receptor, decreasing the probability that released IGF is captured by another IGFBP molecule before receptor binding. This mechanism potentially functions in both autocrine and paracrine regulation, as
PAPP-A
need not be synthesized in a cell to which it adheres. A truncated
PAPP-A
variant without the five short consensus repeats in the C-terminal third of the 1547-residue
PAPP-A
subunit, lacked surface binding. We also show that PAPP-A2, a recently discovered IGFBP-5 proteinase with homology to
PAPP-A
, does not bind cells. This finding allowed further mapping of the
PAPP-A
adhesion site to short consensus repeat modules 3 and 4 by the expression and analysis of nine
PAPP-A
/PAPP-A2 chimeras. Interestingly, the proteolytically inactive, disulfide-bound complex of
PAPP-A
and the proform of eosinophil major basic protein (proMBP),
PAPP-A
.proMBP, shows only weak surface binding, probably because the adhesion site of
PAPP-A
is occupied by heparan sulfate, known to be covalently bound to proMBP. This hypothesis was further substantiated by demonstrating that
heparinase
treatment of
PAPP-A
.proMBP restores surface binding. We finally propose a model in which IGF bioactivity is regulated by reversible cell surface binding of
PAPP-A
, which in turn is regulated by proMBP.
...
PMID:Cell surface targeting of pregnancy-associated plasma protein A proteolytic activity. Reversible adhesion is mediated by two neighboring short consensus repeats. 1237 Jan 76
