Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis

Abstract

Neuropilins (NRP) play a central role in neuronal and blood vessel development as receptors for two ligand types, the semaphorin (SEMA) family of axon guidance modulators and the VEGF family of angiogenesis stimulators. The role of NRPs in axon guidance is well documented but a role in blood vessel development is less so. NRPs mediate normal developmental angiogenesis as shown in mouse and zebrafish models, and pathological angiogenesis in tumors and retinal disease. The ability of two disparate ligand families to bind to the same receptor is unusual but may be explainable by analysis of neuropilin structure. There are two NRP genes, nrp1 and nrp2. The NRPs have a relatively large extracellular domain consisting of sub domains, which are ligand binding sites. VEGF(165) binds to the b1b2 subdomain, SEMA3A and SEMA3F also bind to b1b2 but to a1a2 as well. Mutagenesis studies have identified NRP amino acids that bind VEGF(165) but not SEMA3F. These NRP structural elements might dictate differential SEMA and VEGF(165) binding properties, which in turn regulate angiogenesis. This article reviews the latest information of NRP structure and how structure influences angiogenesis. In addition, the role of NRPs in human cancer is addressed.

SEMA3F (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F)

“…Class-3 semaphorins bind to a1a2 through the Sema domain, Ig-like domain and the C-terminal basic tail, and to b1 through the C-terminal tail. VEGF and heparin bind to b1b2 (review: Geretti et al, 2008). After dimerization NRP2 forms complexes with type-A plexins.…”

“…However, the NRP-interacting protein (NIP) containing a PDZ domain often involved in protein-protein interactions, binds to the last terminal three amino acids (SEA) of NRPs. Neuropilins were independently identified as coreceptors for vascular endothelial growth factor (VEGF) and the semaphorin/neuropilin system is an important regulator of cardiovascular development and angiogenesis (review: Geretti et al, 2008). Class-3 semaphorins, and particularly SEMA3A, have been described as competitors for VEGF 165 binding to NRPs.…”

“…SEMA3F antitumor activity can be impaired by abnormal expression of NRPs that are frequently overexpressed and often associated with poor prognosis and advance disease. Recent excellent reviews cover NRP involvement in cancers (Ellis, 2006;GuttmanRaviv et al, 2006;Bielenberg and Klagsbrun, 2007;Staton et al, 2007;Geretti et al, 2008). The semaphorin pathway could be a target for cancer treatment.…”

Effect of intracortical vascular endothelial growth factor infusion and blockade during the critical period in the rat visual cortex

“…In pathological conditions, VEGFR mediates an antiapoptotic effect through Phosphoinositide 3-kinase (PI3K)-dependent signaling pathways that promote the survival of endothelial cells induced by VEGF (Jin et al, 2000(Jin et al, , 2001Geretti et al, 2008) and is related to the blood-brain barrier (BBB) opening in brain injury Lafuente et al, 2006;Ortuzar et al, 2010). A neuroprotective role for VEGF via VEGFR-2 has also been described (Oosthuyse et al, 2001;Storkebaum et al, 2004;Moser and Humpel, 2005;Ortuzar et al, 2011), which occurs via the PI3k/Akt and the mitogen-activated protein kinase/ERK kinase/extracellular signal-regulated protein kinase (MEK/ERK) pathways (Wick et al, 2002;Kaya et al, 2005).…”

Análise da atividade de CD100 na modulação da ativação de macrófagos e sua infectividade por Leishmania (Leishmania) amazonensis.

“…As semaforinas são proteínas solúveis ou ligadas à membrana sendo inicialmente identificadas como moléculas de quimiorrepulsão no desenvolvimento neuronal, desempenhando um papel crucial na orientação dos axônios (SUZUKI et al, 2003, MIZUI et al, 2009, CH'NG e KUMANOGOH, 2010 , GERETTI et al, 2008, crescimento invasivo de células epiteliais (GIORDANO et al, 2002), progressão de tumor (BIELENBERG e KLAGSBRUN, 2007) e regulação imune (KIKUTANI e KUMANOGOH, 2003, SUZUKI et al, 2008, MIZUI et al, 2009.…”