Integrin α9β1 is a receptor for nerve growth factor and other neurotrophins

Sariyer, Ilker Kudret; Lecht, Shimon; Brown, Meghan C.; Walsh, Erin; Tuszynski, George P.; Safak, Mahmut; Lazarovici, Philip; Marcinkiewicz, Cezary

doi:10.1242/jcs.000232

Cited by 68 publications

(57 citation statements)

References 53 publications

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“…It can mediate cell proliferation through direct binding of nerve growth factor (38) and granulopoiesis (39) and lymphatic cell migration (27) through interactions with granulocyte-colony-stimulating factor and hepatic growth factor, respectively. Whether the amino acids necessary for interactions between ␣9␤1 and these growth factors are common to VEGF remains to be determined, but based on the known diverse ligand binding sequences used by ␣9␤1, it seems unlikely.…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Oommen

Gupta

Vlahakis

2011

Journal of Biological Chemistry

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Integrin ␣9␤1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the ␣9␤1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin ␣9␤1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for ␣9␤1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin ␣9␤1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy.The integrins are a diverse family of transmembrane heterodimeric adhesion receptors. They mediate outside-in and inside-out signaling through cell interactions with the extracellular matrix and in turn facilitate numerous processes such as cell adhesion, migration, and proliferation (1, 2). ␣9␤1 forms a small subfamily of integrins with ␣4␤1 and plays a specialized role in accelerated cell migration, for example more robust compared with ␣3␤1, ␣V␤3, and ␣5␤1 (3). Its biologic role was unclear until genetic deletion of the integrin in mice revealed a novel phenotype manifest by malnutrition and chylothoraces resulting in death 10 -12 days after birth (4). Ultimately, this phenotype was found to result in part from abnormal development of lymphatic valves (5) but also through disrupted direct ␣9␤1-VEGF-C/D interactions (6).The VEGF family of growth factors mediates many separate but overlapping functions, including inflammation and vascular permeability (7, 8), angiogenesis (VEGF-A), lymphangiogenesis (VEGF-C and D) (9), and carcinogenesis (10). VEGF-A undergoes alternative gene splicing resulting in multiple mature forms that share a VEGF homology domain and which interact with a wide array of common and unique partner proteins. VEGF-A165, the most common and well studied VEGF-A isoform, transduces its effects through binding of its canonical receptor, VEGFR-2 (9, 11). Following binding of VEGF-A, VEGFR-2 is autophosphorylated and subsequently internalized to endosomes and is either recycled to the cell surface in a functional state or trafficked to late endosomes and degraded (12).Although VEGF-A signals primarily through the VEGF receptors, it is also able to mediate its effects through interactions with other receptors, including integrins (3, 6, 13). Of particular note, we have reported that integrin ␣9␤1 is able to bind VEGF-C and D directly (6), which appears to explain partly the abnormal lymphatic development in the ␣9-null mouse. Subsequently, we...

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Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Oommen

Gupta

Vlahakis

2011

Journal of Biological Chemistry

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“…Although much is known about the various ligands that can bind to integrin α9β1 to induce cell migration (Yokosaki et al, 1998; Yokasaki and Sheppard, 2000;Vlahakis et al, 2005;Vlahakis et al, 2007;Shinde et al, 2008;Staniszewska et al, 2008), the extent and nature of signaling pathways distal to the activated integrin remain unclear. Fig.…”

Section: Discussionmentioning

confidence: 99%

Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase

Gupta

Vlahakis

2009

Journal of Cell Science

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Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin α9β1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin α9β1 signals migration. We found for the first time that specific ligation of integrin α9β1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin α9β1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-α9β1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin α9 was crucial for integrin-α9β1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin α9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-α9β1-mediated cell migration.

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“…To obtain optimal regeneration from dorsal root ganglion (DRG) neurons on laminin and fibronectin, it was necessary to overexpress ␣1 and ␣5 integrin subunits, which combine with the pool of ␤1 subunit to produce receptors for laminin and fibronectin, promoting axon growth (Condic 2001). In the damaged CNS, there is an upregulation of TN-C; however, TN-C binding integrins, particularly ␣9␤1, are absent in the adult nervous system (Wang et al, 1995;Staniszewska et al, 2008), which may contribute to the inability of neurons to grow through TN-C-rich areas.…”

Section: Introductionmentioning

confidence: 99%

α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration

Andrews¹,

Czvitkovich²,

Dassie³

et al. 2009

J. Neurosci.

147

162

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Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The ␣9␤1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the ␣9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of ␣9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling ␣9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express ␣9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in ␣9 integrinexpressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after ␣9 integrin treatment but remained elevated in control groups.

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Integrin α9β1 is a receptor for nerve growth factor and other neurotrophins

Cited by 68 publications

References 53 publications

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase

α9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration

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