Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling.
ABSTRACT 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.
SourceAvailable from: Enrico Giraudo[Show abstract] [Hide abstract]
ABSTRACT: During organogenesis, patterning is primarily achieved by the combined actions of morphogens. Among these, semaphorins represent a general system for establishing the appropriate wiring architecture of biological nets. Originally discovered as evolutionarily conserved steering molecules for developing axons, subsequent studies on semaphorins expanded their functions to the cardiovascular and immune systems. Semaphorins participate in cardiac organogenesis and control physiological vasculogenesis and angiogenesis, which result from a balance between pro- and anti-angiogenic signals. These signals are altered in several diseases. In this review, we discuss the role of semaphorins in vascular biology, emphasizing the mechanisms by which these molecules control vascular patterning and lymphangiogenesis, as well as in genetically inherited and degenerative vascular diseases.Trends in Molecular Medicine 08/2014; 10(2):1-10. DOI:10.1016/j.molmed.2014.07.005 · 10.11 Impact Factor
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ABSTRACT: Abstract: The semaphorins, discovered over 20 years ago, are a large family of secreted or transmembrane and glycophosphatidylinositol-anchored proteins initially identified as axon guidance molecules crucial for the development of the nervous system. It has now been established that they also play important roles in organ development and function, especially involving the immune, respiratory, and cardiovascular systems, and in pathological disorders, including cancer. During tumor progression, semaphorins can have both pro- and anti-tumor functions, and this has created complexities in our understanding of these systems. Semaphorins may affect tumor growth and metastases by directly targeting tumor cells, as well as indirectly by interacting with and influencing cells from the micro-environment and vasculature. Mechanistically, semaphorins, through binding to their receptors, neuropilins and plexins, affect pathways involved in cell adhesion, migration, invasion, proliferation, and survival. Importantly, neuropilins also act as co-receptors for several growth factors and enhance their signaling activities, while class 3 semaphorins may interfere with this. In this review, we focus on the secreted class 3 semaphorins and their neuropilin co-receptors in cancer, including aspects of their signaling that may be clinically relevant.OncoTargets and Therapy 09/2014; 7:1663—1687. DOI:10.2147/OTT.S37744 · 1.34 Impact Factor
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ABSTRACT: Introduction: Semaphorins have been originally identified as a family of evolutionary conserved soluble or membrane-associated proteins involved in diverse developmental phenomena. This family of proteins profoundly influences numerous pathophysiological processes, including organogenesis, cardiovascular development and immune response. Apart from steering the neural networking process, these are implicated in a broad range of biological operations including regulation of tumor progression and angiogenesis. Areas covered: Members of class 3 semaphorin family are known to modulate various cellular processes involved in malignant transformation. Some of the family members trigger diverse signaling processes involved in tumor progression and angiogenesis by binding with plexin and neuropilin. A better understanding of the various signaling mechanisms by which semaphorins modulate tumor progression and angiogenesis may serve as crucial tool in crafting new semaphorin-based anticancer therapy. These include treatment with recombinant tumor suppressive semaphorins or inhibition of tumor-promoting semaphorins by their specific siRNAs, small-molecule inhibitors or specific receptors using neutralizing antibodies or blocking peptides that might serve as novel strategies for effective management of cancers. Expert opinion: This review focuses on all the possible avenues to explore various members of class 3 semaphorin family to serve as therapeutics for combating cancer.Expert Opinion on Therapeutic Targets 11/2014; 19(3):1-16. DOI:10.1517/14728222.2014.986095 · 4.90 Impact Factor