Intracellular Signaling Mediated by NCAM

NCAM may influence different second messenger systems. Originally, it was found that polyclonal antibodies against L1 and NCAM reduced intracellular levels of the inositol phosphates, IP2 and IP3, while the intracellular level of cAMP was unaffected. The antibodies also reduced intracellular pH and increased intracellular Ca2+ by opening Ca2+-channels in a manner which was sensitive to inhibition by pertussis toxin23. Further insight came from a study showing that NCAM-dependent neurite outgrowth was selectively inhibited in cultures of neurons from fyn knockout mice24. In wild-type cells, fyn was constitutively associated with NCAM140, the focal adhesion kinase, FAK, and became recruited to the NCAM140-fyn complex in response to stimulation with antibodies against the extracellular region of NCAM25. The NCAM140 isoform appears to directly interact with the intracellular domain of the receptor-type protein tyrosine phosphatase RPTPa, and this interaction is important for NCAM triggered activation of fyn26.

The surface mobility of NCAM 140 is higher than that of NCAM18027, suggesting an association of the latter with the cytoskeleton or other stabilizing factors. NCAM 180 is accumulated at sites of cell-to-cell contacts, where the cytoskeleton-membrane linker protein, spectrin, and actin also accumulate. Heteromeric spectrin (aIPI) binds to the intracellular domain of NCAM 180, whereas isolated spectrin subunits bind to both NCAM 180 and NCAM 140. NCAM140/ NCAM180-PI spectrin complexes are located both in lipid rafts and raft-free membrane domains. Activation of NCAM enhances formation of complexes between PKCP2 and NCAM140/NCAM180-spectrin, and results in their redistribution to lipid rafts. This process requires activity of FGF receptors and is necessary for NCAM-mediated neurite outgrowth28. These data support a model in which NCAM-mediated outgrowth requires co-signaling via raft-associated kinases and FGF receptors29 (for a recent review see ref. 30).

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