Figure 6

Proposed working model for the generation of the PSA-carrying NCAM fragment. (a) PSA-carrying NCAM interacts with the FGF receptor and the effector domain (ED) of non-phosphorylated MARCKS which sequesters calmodulin to the plasma membrane. Binding of NCAM ligands to PSA-NCAM leads to dissociation of the FGF receptor and PSA-NCAM and detachment of the PSA moiety from MARCKS followed by activation of the FGF receptor, PLC, PKC, and PI3K. PKC-mediated phosphorylation of the MARCKS effector domain triggers the release of membrane-bound MARCKS and dissociation of calmodulin from MARCKS. Free calmodulin binds to NOS leading to activation of NOS and production of NO, which is released into the extracellular space. S-nitrosylation of MMP-9 by NO leads to activation of MMP-9 and subsequent activation of MMP2 and cleavage of PSA-NCAM by active MMP2. After cleavage, the PSA-carrying NCAM fragment is internalized, transported to endosomes and released from the endosomal membrane into the cytoplasm involving calmodulin and imported calmodulin-independently from the cytoplasm into the nucleus. (b) The MARCKS-derived ED peptide like endogenous stimuli affects the interaction of the PSA moiety and MARCKS and thereby not only triggers the dissociation of the FGF receptor and PSA-NCAM, the activation of the FGF receptor, PLC and PKC and phosphorylation of the MARCKS effector domain, but also the activation of PLD, which produces phosphatidic acid. Activation of PLD and production of phosphatidic acid may lead to inhibition of calmodulin to activate NOS, but triggers the direct activation of MMP2 which cleaves PSA-NCAM.