The Cytoplasmic Domain of the Integrin α9 Subunit Requires the Adaptor Protein Paxillin to Inhibit Cell Spreading but Promotes Cell Migration in a Paxillin-independent Manner

Young, Bradford A.; Taooka, Yasuyuki; Liu, Shouchun; Askins, Karen J.; Yokosaki, Yasuyuki; Thomas, Sheila M.; Sheppard, Dean

doi:10.1091/mbc.12.10.3214

Cited by 74 publications

(114 citation statements)

References 24 publications

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“…A direct association of paxillin with ␤1-integrin (231, 259), ␣4-and ␣9-subunit cytoplasmic tails has been reported (153,155,156,322). The ␣4-and ␣9-integrin binding site has been localized to a region of paxillin amino-terminal and partially overlapping LD4 (154).…”

Section: Other Paxillin Binding Partnersmentioning

confidence: 97%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

550

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Molecular scaffold or adaptor proteins facilitate precise spatiotemporal regulation and integration of multiple signaling pathways to effect the optimal cellular response to changes in the immediate environment. Paxillin is a multidomain adaptor that recruits both structural and signaling molecules to focal adhesions, sites of integrin engagement with the extracellular matrix, where it performs a critical role in transducing adhesion and growth factor signals to elicit changes in cell migration and gene expression.

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Section: Other Paxillin Binding Partnersmentioning

confidence: 97%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

550

728

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“…␣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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

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.

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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...

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“…The integrin ␣9 subunit forms a single heterodimer with ␤1 and is expressed in epithelial cells, smooth and skeletal muscle, neutrophils, and a subset of endothelial cells (5,6). In vitro, the principal demonstrated function of ␣9␤1 is acceleration of cell migration, an effect that depends on unique sequences within the ␣9 cytoplasmic domain (7,8).…”

mentioning

confidence: 99%

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

Vlahakis

Young

Atakilit

et al. 2005

Journal of Biological Chemistry

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Mice homozygous for a null mutation of the integrin ␣9 subunit die 6 -12 days after birth from bilateral chylothoraces suggesting an underlying defect in lymphatic development. However, until now the mechanisms by which the integrin ␣9␤1 modulates lymphangiogenesis have not been described. In this study we show that adhesion to and migration on the lymphangiogenic vascular endothelial growth factors (VEGF-C and -D) are ␣9␤1-dependent. Mouse embryonic fibroblasts and human colon carcinoma cells (SW-480) transfected to express ␣9␤1 adhered and/or migrated on both growth factors in a concentration-dependent fashion, and both adhesion and migration were abrogated by anti-␣9␤1 function-blocking antibody. In SW-480 cells, which lack cognate receptors for VEGF-C and -D, both growth factors induced ␣9␤1-dependent Erk and paxillin phosphorylation. Human microvascular endothelial cells, which express both ␣9␤1 and VEGF-R3, also adhered to and migrated on both growth factors, and both responses were blocked by anti-␣9␤1 antibody. Furthermore, in a solid phase binding assay recombinant VEGF-C and -D bound to purified ␣9␤1 integrin in a dose-and cationdependent fashion showing that VEGF-C and VEGF-D are ligands for the integrin ␣9␤1. The interaction between ␣9␤1 and VEGF-C and/or -D may begin to explain the abnormal lymphatic phenotype of the ␣9 knock-out mice.

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The Cytoplasmic Domain of the Integrin α9 Subunit Requires the Adaptor Protein Paxillin to Inhibit Cell Spreading but Promotes Cell Migration in a Paxillin-independent Manner

Cited by 74 publications

References 24 publications

Paxillin: Adapting to Change

Paxillin: Adapting to Change

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

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

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