Neuropilin-2 regulates 6 1 integrin in the formation of focal adhesions and signaling

Department of Cancer Biology, University of Massachusetts Medical School Worcester, MA 01605, USA.
Journal of Cell Science (Impact Factor: 5.43). 01/2012; 125(Pt 2):497-506. DOI: 10.1242/jcs.094433
Source: PubMed


The neuropilins (NRPs) contribute to the function of cancer cells in their capacity as VEGF receptors. Given that NRP2 is induced in breast cancer and correlates with aggressive disease, we examined the role of NRP2 in regulating the interaction of breast cancer cells with the ECM. Using epithelial cells from breast tumors, we defined NRP2(high) and NRP2(low) populations that differed in integrin expression and adhesion to laminin. Specifically, the NRP2(high) population adhered more avidly to laminin and expressed high levels of the α6β1 integrin than the NRP2(low) population. The NRP2(high) population formed numerous focal adhesions on laminin that were not seen in the NRP2(low) population. These results were substantiated using breast carcinoma cell lines that express NRP2 and α6β1 integrin. Depletion experiments revealed that adhesive strength on laminin but not collagen is dependent on NRP2, and that VEGF is needed for adhesion on laminin. A specific interaction between NRP2 and α6β1 integrin was detected by co-immunoprecipitation. NRP2 is necessary for focal adhesion formation on laminin and for the association of α6β1 integrin with the cytoskeleton. NRP2 also facilitates α6β1-integrin-mediated activation of FAK and Src. Unexpectedly, we discovered that NRP2 is located in focal adhesions on laminin. The mechanism by which NRP2 regulates the interaction of α6β1 integrin with laminin to form focal adhesions involves PKC activation. Together, our data reveal a new VEGF-NRP2 signaling pathway that activates the α6β1 integrin and enables it to form focal adhesions and signal. This pathway is important in the pathogenesis of breast cancer.

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    • "neuroblastoma) frequently express NRP-2 [29], and NRP-2 expression is also elevated in high-grade prostate cancers with PTEN loss [30], a frequent event in glioblastoma [31]. NRP-2 is essential for breast cancer tumor initiation [32], where it is involved in the formation of focal adhesions [33] and is associated with metastasis and poor prognosis [34]. NRP-2 also promotes the invasion and migration of thyroid cancer cells in vitro, an effect that could be blocked by a neutralizing anti-NRP-2 antibody [35]. "
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    • "Here we expand those studies by observing the association between Nrp1 and p130Cas, and their widespread colocalization. Nrp2 was also reported to be involved in the formation of FAs through the regulation of the activity of integrin a 6 b 1 , and was shown to be abundant in FAs [39]. Interestingly, FlnA had been reported to regulate the recycling of the calcitonin receptor (CTR), a G-protein coupled receptor that is involved in the maintenance of calcium homeostasis [40]. "
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