Abstract
By physically interacting with beta-1 integrins, the NG2 proteoglycan enhances activation of the integrin heterodimers. In glioma cells, co-localization of NG2 and α3β1 integrin in individual cells (cis interaction) can be demonstrated by immunolabeling, and the NG2-integrin interaction can be confirmed by co-immunoprecipitation. NG2-dependent integrin activation is detected via use of conformationally sensitive monoclonal antibodies that reveal the activated state of the beta-1 subunit in NG2-positive versus NG2-negative cells. NG2-dependent activation of beta-1 integrins triggers downstream activation of FAK and PI3K/Akt signaling, resulting in increased glioma cell proliferation, motility, and survival. Similar NG2-dependent cis activation of beta-1 integrins occurs in microvascular pericytes, leading to enhanced proliferation and motility of these vascular cells. Surprisingly, pericyte NG2 is also able to promote beta-1 integrin activation in closely apposed endothelial cells (trans interaction). Enhanced beta-1 signaling in endothelial cells promotes endothelial maturation by inducing the formation of endothelial junctions, resulting in increased barrier function of the endothelium and increased basal lamina assembly. NG2-dependent beta-1 integrin signaling is therefore important for tumor progression by virtue of its affects not only on the tumor cells themselves, but also on the maturation and function of tumor blood vessels.
Highlights
The membrane-spanning NG2 proteoglycan (Figure 1), known as chondroitin sulfate proteoglycan-4 (CSPG4), has only limited signal transducing capability of its own [1,2]
Most research has been focused on NG2 expression in the case of gliomas and melanomas, since NG2 is often found on the tumor cells themselves in these neoplasms
Because NG2 is expressed by several elements of the tumor stroma, including macrophages and microvascular pericytes [28], NG2 expression is relevant to many
Summary
The membrane-spanning NG2 proteoglycan (Figure 1), known as chondroitin sulfate proteoglycan-4 (CSPG4), has only limited signal transducing capability of its own [1,2]. Studies with a number of different immature or progenitor cell types indicate that NG2-enhanced signaling processes promote cell proliferation, motility, and survival, all of which are valuable properties for progenitor cells [16,17]. These characteristics would be expected to benefit tumor progression, and expression of NG2 is correlated with tumor malignancy and poor patient outcome in several types of cancer [3,18,19,20,21,22,23,24,25,26].
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