Insulin and IGF1 modulate turnover of polysialylated neural cell adhesion molecule (PSA–NCAM) in a process involving specific extracellular matrix components

Abstract

Cellular interactions mediated by the neural cell adhesion molecule (NCAM) are critical in cell migration, differentiation and plasticity. Switching of the NCAM-interaction mode, from adhesion to signalling, is determined by NCAM carrying a particular post-translational modification, polysialic acid (PSA). Regulation of cell-surface PSA-NCAM is traditionally viewed as a direct consequence of polysialyltransferase activity. Taking advantage of the polysialyltransferase Ca 2+ -dependent activity, we demonstrate in TE671 cells that downregulation of PSA-NCAM synthesis constitutes a necessary but not sufficient condition to reduce cell-surface PSA-NCAM; instead, PSA-NCAM turnover required internalization of the molecule into the cytosol. PSA-NCAM internalization was specifically triggered by collagen in the extracellular matrix (ECM) and prevented by insulin-like growth factor (IGF1) and insulin. Our results pose a novel role for IGF1 and insulin in controlling cell migration through modulation of PSA-NCAM turnover at the cell surface.

Distribution of PSA-NCAM in normal, Alzheimer’s and Parkinson’s disease human brain

“…Using western blotting we confirmed that both antibodies label proteins in the 200-220-kDa range. Post-translational addition of different PSA chain lengths to the NCAM protein results in variable molecular weights within this range, which is consistent with previous reports of PSA-NCAM size (Mikkonen et al, 1999;Monzo et al, 2013) (Fig. 1D).…”

Pregnancy associated plasma protein-aa (Pappaa) regulates photoreceptor synaptic development to mediate visually guided behavior

“…Pappaa could act in an autocrine manner to stimulate postsynaptic IGF1R signaling in OFF bipolar cells. Postsynaptically, IGF1 has been shown to promote dendritic growth (Camarero et al, 2001;Cheng et al, 2003;Shi et al, 2005;Carlson et al, 2014), membrane receptor and channel stability through the activity of synaptic scaffolding proteins (Corvin et al, 2012;Della Sala et al, 2016), and the development and maintenance of synaptic connections via cell adhesion molecules (Bonfanti, 2006;Monzo et al, 2013). Although we did not observe defects in dendritic size (Fig.…”

Is Polysialylated NCAM Not Only a Regulator during Brain Development But also during the Formation of Other Organs?

“…A comparable interrelation was also observed in the postnatal tunica albuginea [71], which enclose the testis and consists of fibroblast, myofibroblast and smooth muscle cells and extracellular matrix components like collagen [82]. An in cellulo study by Curtis and co-workers described a possible explanation for the contrarily-regulated amounts of polysialylated NCAM and collagen [83]. They observed an internalization and desialylation of polySia-NCAM, specifically triggered by extracellular collagen.…”

“…( B ) With increasing amounts of collagen the polysialylation of smooth muscle cells stops. Based on cell culture experiments in the lab of Curtis showing that collagen induces the internalization of polySia-NCAM and degradation of polySia chains [83], a functional relationship between increasing amount of collagen and decreasing amount of polySia-NCAM was discussed [71]. …”