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: UNIPROT:P31749 (
AKT
)
22,954
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of
pregnancy-associated plasma protein-A
(
PAPP-A
), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice.
PAPP-A
mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific
PAPP-A
expression in fat accumulation, wild-type (WT) and
PAPP-A
knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and
PAPP-A
KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of
PAPP-A
KO compared with WT mice. After 20 wk on HFD, phosphorylation of
AKT
, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in
PAPP-A
KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of
PAPP-A
KO mice. These data establish fat depot-specific expression of
PAPP-A
and indicate preferential impact of
PAPP-A
deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus,
PAPP-A
may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities.
...
PMID:Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet. 2404 68
The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic. We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase,
pregnancy-associated plasma protein-A
(
PAPP-A
).
PAPP-A
associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of
PAPP-A
would suppress excessive local IGF signaling in tissues where this is caused by increased
PAPP-A
proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of
PAPP-A
. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (
AKT
phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of
PAPP-A
. We further showed that mAb 1/41 is effective towards
PAPP-A
bound to cell surfaces, and that it is capable of inhibiting
PAPP-A
activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced
AKT
phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor.
PAPP-A
targeting thus represents an alternative therapeutic strategy for inhibiting IGF receptor signaling.
...
PMID:Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. 2457 90
