The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1

Vlahakis, Nicholas E.; Young, Bradford A.; Atakilit, Amha; Sheppard, Dean

doi:10.1074/jbc.m412816200

Cited by 181 publications

(167 citation statements)

References 49 publications

(52 reference statements)

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…Previous studies using the ␣9␤1 integrin blocking antibody, Y9A2, have successfully abolished ␣9␤1 substrate binding (Vlahakis et al, 2005(Vlahakis et al, , 2007. PC12 cells, either untransfected or transfected with ␣9 constructs (extracellular domain) and grown on laminin, extended long neurites unaffected by the presence of the ␣9␤1 integrin blocking antibody (Fig.…”

Section: Expression Of ␣9 Integrin In Pc12 Cells Overcomes Inhibitionmentioning

confidence: 99%

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

Andrews¹,

Czvitkovich²,

Dassie³

et al. 2009

J. Neurosci.

146

162

View full text Add to dashboard Cite

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.

show abstract

Section: Expression Of ␣9 Integrin In Pc12 Cells Overcomes Inhibitionmentioning

confidence: 99%

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

Andrews¹,

Czvitkovich²,

Dassie³

et al. 2009

J. Neurosci.

146

162

View full text Add to dashboard Cite

show abstract

“…4b) (31), and adhere to and migrate on ␣9␤1 ligands (31). Human microvascular endothelial cells (HMVECs) expressed four Kir subunits that are also expressed in MEFs, including Kir4.2 ( Fig.…”

Section: Inward Rectifier Potassium Channel Function Is Important For ␣9mentioning

confidence: 99%

The α9β1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

deHart¹,

Jin

McCloskey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The ␣9␤1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the ␣9 cytoplasmic domain. We now show that SSAT enhances ␣9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K ؉ ion efflux through inward-rectifier K ؉ (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited ␣9-dependent cell migration. ␣9␤1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an ␣9␤1 ligand. These results identify a pathway through which the ␣9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.T he ␣9␤1 integrin is widely expressed and binds to a number of ligands, including the extracellular matrix protein tenascin-C, the vascular cell adhesion molecule, VCAM-1, and several members of the ADAM family (1-3). ␣9␤1 mediates enhanced cell migration, an effect that specifically depends on the ␣9 cytoplasmic domain (4, 5). The closely related integrin ␣4 subunit also accelerates cell migration, through reversible interaction with the scaffolding protein, paxillin (6, 7). The mechanism by which the ␣9 subunit cytoplasmic domain accelerates cell migration is completely different (4, 5), and requires binding of the enzyme, spermidine/ spermine-N 1 -acetyltransferase (SSAT) (5). The mechanisms by which SSAT binding modulates migration were until now unknown. SSAT specifically catalyzes catabolism of the higher order polyamines, spermidine and spermine, to the lower order polyamine, putrescine (8), thereby increasing intracellular levels of putrescine, and decreasing those of spermidine and spermine (9, 10).Spermine and spermidine are potent blockers of outward potassium (K ϩ ) currents from inward rectifier K ϩ (Kir) channels (11-13). These channels conduct larger inward currents at membrane voltages below the resting potential than outward currents at more positive voltages. The long, positively charged polyamines, spermine (ϩ4) or spermidine (ϩ3), mediate rectification by binding to negatively charged residues in the channel pore (12,14). The catabolized polyamine putrescine (ϩ2) is less effective at blocking outward flow of K ϩ ions (11, 12). Although Kir channels have been implicated in the regulation of many different physiological processes, including heart rate and membrane excitability (15), there are currently no reports suggesting their involvement in the regulation of cell migration. However, numerous studies have suggested that K ϩ efflux is a critical factor in modulating cell migration (16)(17)(18)(19). In this study, we show that both the catalytic activity of SSAT and the downstream catabolism of polyamines are specifically required for ␣9...

show abstract

“…Integrin ␣9␤1 is currently viewed as a major integrin associated with lymphangiogenesis because integrin ␣9-KO mice develop respiratory failure and postnatal death caused by chylothorax (12). It has also been shown that ␣9 integrin binds VEGF-C directly (13). Moreover, inhibition of ␣5␤1 integrin reduced lymphangiogenesis in inflamed airways after Mycoplasma pulmonis infection and in corneal inflammation (14,15).…”

mentioning

confidence: 99%

Deletion of Tetraspanin CD9 Diminishes Lymphangiogenesis in Vivo and in Vitro

Iwasaki

Takeda

Maruyama

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: The molecular mechanisms regulating lymphangiogenesis remain unclear. Results: Tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis. Conclusion: Deletion of CD9 diminished lymphangiogenesis in mice and humans. Significance: Given that CD9 mediates inflammation and tumor progression, CD9 might be a key component not only in tumor metastasis, but also in inflammation.

show abstract

The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1

Cited by 181 publications

References 49 publications

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

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

The α9β1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

Deletion of Tetraspanin CD9 Diminishes Lymphangiogenesis in Vivo and in Vitro

Contact Info

Product

Resources

About