The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added 125 I-hIGFBP-2 specifically bound to the cells. Bound 125 I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for 5 1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0·01), and of the p42/44 MAP-kinases of up to 40% (P<0·01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0·05), and reduced proliferation by 24% (P<0·01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with 5 1-integrin.
Background: Formula milk-fed infants show faster rates of growth and weight gain than do breastfed infants, and they have higher concentrations of insulin-like growth factor I (IGF-I). Objective: Our objective was to determine the influence of IGF-I concentrations on gains in weight, length, body mass index (BMI), and adiposity in the first year of life. Design: IGF-I concentrations were measured in 953 capillary blood samples from 675 unselected infants at ages 3 and 12 mo. These infants were born between 2002 and 2008 in one center and were participating in a prospective longitudinal birth cohort. Weight, length, and 4 skinfold thicknesses as an indicator of adiposity were measured at ages 0, 3, and 12 mo. Analyses were adjusted for age and sex. Results: Infants who were formula milk-fed had higher IGF-I concentrations at 3 mo, and they showed greater gains in weight, length, BMI, and adiposity between age 3 and 12 mo. IGF-I concentrations at 3 mo were unrelated to subsequent overall weight gain (P = 0.5). However, higher IGF-I concentrations at age 3 mo predicted greater subsequent gains in body length (P , 0.001 and P = 0.007 in formula milk-fed and breastfed infants, respectively) and slower gains in BMI (P , 0.001 and P = 0.004, respectively) and adiposity (P = 0.03 and P = 0.003, respectively). Conclusions: Our findings support a key role for IGF-I in the partitioning of overall infant weight gain into statural growth compared with adiposity. In formula milk-fed infants, higher IGF-I concentrations may lead to faster gains in length; however, other mechanisms likely explain their faster gains in weight, BMI, and adiposity. Am J Clin Nutr 2009;90:156-61.
BackgroundThere is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.MethodsWe assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.ResultsA large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.ConclusionsConcomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.
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