Chondroitin sulphate‐modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas‐mediated pathway

Abstract

Neuropilin 1 (NRP1), a non-tyrosine kinase receptor for vascular endothelial growth factor and class 3 Semaphorins, is highly expressed in many human tumour cell lines, but its function is poorly understood. Here, we describe the expression of a new chondroitin sulphate-modified NRP1 (NRP1-CS) in human tumour cell lines. Expression of a non-modifiable NRP1 mutant (S612A) in U87MG human glioma cells results in enhanced invasion in three dimensions (3D), whereas wild-type NRP1 has no effect. Furthermore, the S612A NRP1 cells show a significant increase in p130Cas tyrosine phosphorylation compared with control and wild-type NRP1 cells. Silencing of p130Cas in S612A NRP1 cells resulted in a loss of increased invasive phenotype. Interestingly, p130Cas silencing does not inhibit basal 3D invasion, but leads to a mesenchymal to amoeboid transition. Biopsies from both low-and high-grade human gliomas show strong expression of NRP1, and little expression of NRP1-CS. Our data establish distinct roles for NRP1 and NRP1-CS in modulating a new NRP1-p130Cas signalling pathway contributing to glioblastoma cell invasion in 3D. Keywords: growth factors; VEGF; metastasis; proteoglycan EMBO reports (2008) 9, 983-989.

Neuropilin-1 Signaling through p130Cas Tyrosine Phosphorylation Is Essential for Growth Factor-Dependent Migration of Glioma and Endothelial Cells

“…Although Src directly phosphorylates p130 Cas at focal adhesions within a macromolecular complex requiring focal adhesion kinase (FAK) (5, 26), we detected no changes in the level of tyrosine phosphorylation of Src or FAK in U87MG cells expressing S612A NRP1 (9). Furthermore, NRP1 siRNA had no effect on growth factor-stimulated FAK autophosphorylation (Y397) (data not shown), and FAK siRNA treatment had no effect on ligand-stimulated p130 Cas tyrosine phosphorylation (Fig.…”

“…Cas , which was required for cell motility (9), raising the possibility that NRP1 could be an important endogenous mediator of p130…”

“…Though the precise cellular functions of NRP1 have yet to be elucidated, there is a growing body of evidence supporting a key role for NRP1 in the migration of both endothelial and tumor cells (9,11,15,19). NRP1 is thought to act as a coreceptor for VEGF by forming complexes with the VEGF receptor tyrosine kinase (RTK) VEGFR2.…”

“…Cas (9). Here, we investi-gated the role of NRP1 in p130 Cas signaling in chemotactic responses to growth factors.…”

NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer

“…55,56 BCAR1 signaling has also been associated with cell proliferation, survival, and migration/invasion in many tumor types besides breast cancer, including ovarian and prostate cancer, glioblastoma, melanoma, and hematopoietic malignancies. 11,12,17,27,[57][58][59][60][61][62][63] Accordingly, a great abundance of BCAR1 tyrosine-and serine/threonine-phosphorylated peptides have been detected in a wide variety of cancers (phosphosite.org) (Fig. 1).…”