Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling

Muhl, Lars; Folestad, Erika; Gladh, Hanna; Wang, Yixin; Moessinger, Christine; Jakobsson, Lars; Eriksson, Ulf

doi:10.1242/jcs.200493

Cited by 50 publications

(49 citation statements)

References 48 publications

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“…Similar to the involvement of Semaphorin ligands, the possibility remains that NRP TM dimerization is not required but may somehow modulate HH signaling. It is also possible that NRP interactions with other TM proteins, such as VEGF receptors, Plexins, FGF receptors, or PDGF receptors, may contribute to HH signal promotion (67,81), although many of these receptors interact with NRP1 through its extracellular domain, which, as our data indicate, is dispensable for NRP1 function in HH signaling. This contrasts with the extracellular domain, which is required for Semaphorin signaling, and a conserved SEA motif that is required for VEGF signaling.…”

Section: Identification Of a Cytoplasmic Motif In Nrp1 That Mediates mentioning

confidence: 75%

Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif

Pinskey¹,

Franks

McMellen

et al. 2017

Journal of Biological Chemistry

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Hedgehog (HH) signaling critically regulates embryonic and postnatal development as well as adult tissue homeostasis, and its perturbation can lead to developmental disorders, birth defects, and cancers. Neuropilins (NRPs), which have well-defined roles in Semaphorin and VEGF signaling, positively regulate HH pathway function, although their mechanism of action in HH signaling remains unclear. Here, using luciferase-based reporter assays, we provide evidence that NRP1 regulates HH signaling specifically at the level of GLI transcriptional activator function. Moreover, we show that NRP1 localization to the primary cilium, a key platform for HH signal transduction, does not correlate with HH signal promotion. Rather, a structure-function analysis suggests that the NRP1 cytoplasmic and transmembrane domains are necessary and sufficient to regulate HH pathway activity. Furthermore, we identify a previously uncharacterized, 12-amino acid region within the NRP1 cytoplasmic domain that mediates HH signal promotion. Overall, our results provide mechanistic insight into NRP1 function within and potentially beyond the HH signaling pathway. These insights have implications for the development of novel modulators of HH-driven developmental disorders and diseases.

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Section: Identification Of a Cytoplasmic Motif In Nrp1 That Mediates mentioning

confidence: 75%

Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif

Pinskey¹,

Franks

McMellen

et al. 2017

Journal of Biological Chemistry

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“…NRP1 is capable of binding to a broad repertoire of ligands, accounting for its diverse biological functions. First identified as the coreceptor for the secreted class III Semaphorins, such as Semaphorin 3A (Sema3A), 51 NRP1 was later shown to bind to a variety of growth factors, most notably VEGF 165 , as well as others including transforming growth factor beta, 52 53 platelet-derived growth factors C and D, 54 55 and c-Met. 56 Interestingly, recent studies have revealed that NRP1 also binds to extracellular microRNA/AGO2 complexes and facilitates their internalization, 57 adding another mechanism by which NRP1 modulates cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Chuckran

Liu

Bruno

et al. 2020

J Immunother Cancer

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Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+ T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+ T cell responses. Emerging data suggest that NRP1 restricts CD8+ T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.

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“…Nrp1 is a co-receptor for multiple secreted factors such as semaphorins [ 14 ], VEGF-A [ 15 ], HGF [ 16 ], Hedgehogs [ 17 ], EGF [ 18 ], and PDGFBB [ 19 ] and TGFβs [ 20 ]. Due to its numerous co-receptor roles, Nrp1 participates in pleiotropic functions in many organs in a cell type-selective manner to modulate proliferation, migration, and survival.…”

Section: Introductionmentioning

confidence: 99%

Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy

et al. 2017

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Glioblastoma (GBM) is a rapidly progressive brain cancer that exploits the neural microenvironment, and particularly blood vessels, for selective growth and survival. Anti-angiogenic agents such as the vascular endothelial growth factor-A (VEGF-A) blocking antibody bevacizumab yield short-term benefits to patients due to blood vessel regression and stabilization of vascular permeability. However, tumor recurrence is common, and this is associated with acquired resistance to bevacizumab. The mechanisms that drive acquired resistance and tumor recurrence in response to anti-angiogenic therapy remain largely unknown. Here, we report that Neuropilin-1 (Nrp1) regulates GBM growth and invasion by balancing tumor cell responses to VEGF-A and transforming growth factor βs (TGFβs). Nrp1 is expressed in GBM cells where it promotes TGFβ receptor internalization and signaling via Smad transcription factors. GBM that recur after bevacizumab treatment show down-regulation of Nrp1 expression, indicating that altering the balance between VEGF-A and TGFβ signaling is one mechanism that promotes resistance to anti-angiogenic agents. Collectively, these data reveal that Nrp1 plays a critical role in balancing responsiveness to VEGF-A versus TGFβ to regulate GBM growth, progression, and recurrence after anti-vascular therapy.

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Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling

Cited by 50 publications

References 48 publications

Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif

Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif

Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy

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