α6β4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3β1 integrin

Russell, Alan J.; Fincher, Edgar F.; Millman, Linda; Smith, R. Lane; Vela, Veronica; Waterman, Elizabeth A.; Dey, Clara N.; Guide, Shireen V.; Weaver, Valerie M.; Marinkovich, M. Peter

doi:10.1242/jcs.00663

Cited by 126 publications

(127 citation statements)

References 53 publications

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“…Indeed, overexpression of ␤4 in breast cancer cells normally lacking ␣6␤4 led to increased ECM-independent chemotaxis and invasion and a functionblocking anti-␣6␤4 mAb inhibited migration of colon carcinoma cells on laminin-1 (14). Epidermal growth factor-induced migration was the result of HDs down-regulation (43) and was even actively promoted by ␣6␤4 due to rac1 stimulation (44 (20 M) and anti-integrin mAbs as described in Fig. 7.…”

Section: Discussionmentioning

confidence: 91%

Integrin α6β4-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes

Hintermann

Yang

O’Sullivan

et al. 2005

Journal of Biological Chemistry

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Keratinocyte integrins ␣6␤4 and ␣3␤1 bind laminin-5, a component of basement membranes. We previously demonstrated that in keratinocytes, haptotactic migration on laminin-5 was stimulated by anti-␤1 integrinactivating antibody TS2/16, whereas antibodies to ␣6 and ␤4, respectively, blocked TS2/16-induced, ␣3␤1-dependent migration. Moreover, ␣6␤4-associated haptotaxis inhibition was linked to a phosphatidylinositol 3-kinase (PI3K) pathway and required erbB2 activation. erbB2, the ligand-less member of the epidermal growth factor receptor family, was shown to form a complex with the hemidesmosomal integrin ␣6␤4. Here, we demonstrate that ␣6␤4 inhibitory effects on haptotaxis are abolished by an anti-E-cadherin antibody, which interferes with cell-cell adhesion. Furthermore, antibodies to ␣6 and ␤4 stimulated adhesion to an E-cadherin-Fc recombinant protein. In addition, anti-␣6/␤4 antibodies increased colony size in plated cells, stimulated cell-cell aggregation, and up-regulated E-cadherin localization to cell-cell contacts. These effects were abolished when erbB2 or PI3K were blocked. These results indicate that stimulation of ␣6␤4 increases E-cadherin-mediated cellcell adhesion and that this mechanism depends on erbB2 activation. The molecule that links ␣6␤4 with Ecadherin may be the small GTPase cdc42, an effector of PI3K, because dominant-negative cdc42 abolished the inhibitory effect of anti-␣6/␤4 antibodies and increased basal migration, whereas constitutively active cdc42 prevented the TS2/16-induced increase in haptotaxis. These findings suggest a model whereby ␣6␤4 can augment cell-cell adhesion and slow down haptotaxis over laminin-5 and point to the ␣6␤4-erbB2 heterodimer as an important signaling complex for the formation of cohesive keratinocyte layers.

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Section: Discussionmentioning

confidence: 91%

Integrin α6β4-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes

Hintermann

Yang

O’Sullivan

et al. 2005

Journal of Biological Chemistry

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“…Indeed, here we show that ␣3 integrin supports Transwell migration of prostate cancer cells on laminin-332. Interestingly, in keratinocytes, whether ␣6␤4 integrin binds to laminin-332 may determine whether these cells migrate as collective sheets or in a more mesenchymal mode in response to epidermal growth factor (42). Thus, ZEB1, by repressing ITGB4, as well as CDH1, may contribute to a change in the mode of cell migration from collective to single cell.…”

Section: Discussionmentioning

confidence: 99%

ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells*

Drake¹,

Barnes²,

Madsen³

et al. 2010

Journal of Biological Chemistry

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Metastasis involves the invasion of cancer cells across both the extracellular matrix and cellular barriers, and an evolving theme is that epithelial-to-mesenchymal transition (EMT) may mediate invasive cellular behavior. Previously, we isolated and analyzed a subpopulation of PC-3 prostate cancer cells, TEM4-18, and found that these cells both invaded an endothelial barrier more efficiently and exhibited enhanced metastatic colonization in vivo. Transendothelial migration of these cells depended on expression of ZEB1, a known regulator of EMT. Surprisingly, these cells were much less invasive than parental PC-3 cells in assays that involve matrix barriers. Here, we report that TEM4-18 cells express significantly reduced levels of two subunits of laminin-332 (␤3 and ␥2) and that exogenous laminin-332, or co-culture with laminin-332-expressing cells, rescues the in vitro invasion phenotype in these cells. Stable knockdown of ZEB1 in prostate cancer cells up-regulated LAMC2 and ITGB4 mRNA and protein and resulted in a concomitant increase in Transwell migration. Using chromatin immunoprecipitation (ChIP), we show that ZEB1 directly interacts with the promoters of LAMC2 and ITGB4. These results provide a novel molecular basis for reduced laminin-332 observed in clinical prostate cancer specimens and demonstrate a context-dependent role for EMT in invasive cellular behavior.Metastasis involves the invasion of cancer cells across natural barriers such as basement membranes, interstitial matrix, and the endothelium. Considerable effort over the past decades has defined a number of mechanisms that contribute to the invasive behavior of metastatic cancer cells such as elevated secretion of matrix-degrading enzymes, altered expression of matrix components or their receptors, and increased motility in response to tumor microenvironmental cues. Epithelial-to-mesenchymal transition (EMT) 3 is a mechanism involved in multiple aspects of mammalian development, such as gastrulation and formation of the neural crest, whereby cells lose epithelial identity and gain the ability to move to distant sites in the organism and thus is an attractive paradigm for understanding metastasis (1). Although abundant experimental and some clinical evidence for EMT in cancer exists, the extent to which this mechanism contributes to metastasis remains controversial (2). Although EMT has been most thoroughly investigated in relation to its role in invasion of basement membranes and interstitial matrix, less is known about how it might be involved in later steps of metastasis such as extravasation and colonization (survival and proliferation at distant sites).We recently isolated a subpopulation of the PC-3 prostate cancer cell line, TEM4-18, that was proficient in transendothelial migration and displayed hallmarks of EMT (3). We found that TEM4-18 cells differentially express a dual zinc finger homeodomain transcription factor ZEB1 (also known as ZFHX1a, ␦EF1, or TCF-8), which represses a variety of epithelial genes in TEM4-18 cells and has bee...

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“…Extinction was measured at 450 nm using an ELISA plate reader. Cell migration was assessed by standard scratch assays as previously described (Russell et al, 2003). Confluent HRMEC and HDMEC were cultured in unsupplemented cell culture medium over night.…”

Section: Methodsmentioning

confidence: 99%

Norrin Promotes Vascular Regrowth after Oxygen-Induced Retinal Vessel Loss and Suppresses Retinopathy in Mice

Ohlmann¹,

Seitz²,

Braunger³

et al. 2010

J. Neurosci.

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Norrin is a secreted protein that is involved in retinal angiogenesis and activates the Wnt-signaling pathway. We studied the role of Norrin in microvascular endothelial cells in vitro, and in a mouse model of retinopathy characterized by oxygen-induced vascular loss followed by hypoxia-induced pathological neovascularization. Recombinant Norrin significantly increased proliferation, viability, migration, and tube formation in vitro. Two independent transgenic mouse strains with ectopic overexpression of Norrin from the lens (␤B1-CrystallinNorrin), or the retinal pigment epithelium (Rpe65-Norrin) were generated and exposed to high oxygen. Following oxygen treatment, vascular loss was significantly smaller in retinae of transgenic mice from both strains as compared to wild-type littermates. In addition, the anatomical correct regrowth of vessels was significantly increased, while pathological neovascularization was suppressed. In vitro and in vivo effects of Norrin could be blocked by adding DKK (Dickkopf)-1, an inhibitor of Wnt/␤-catenin signaling. Treatment of microvascular endothelial cells with Norrin caused a substantial increase in the expression of angiopoietin-2 (Ang-2). When inhibitory antibodies against Ang-2 were added to Norrin, the proliferative effects of Norrin were significantly suppressed. We conclude that Norrin is a potent factor to induce angiogenesis in microvascular endothelial cells, which has the distinct potential to suppress the damaging effects of oxygen-induced retinopathy in vivo. The effects of Norrin appear to be mediated, at least partially, via the induction of Ang-2.

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α6β4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3β1 integrin

Abstract: Summaryα6β4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3β1 integrin

Cited by 126 publications

References 53 publications

Integrin α6β4-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes

Integrin α6β4-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes

ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells*

Norrin Promotes Vascular Regrowth after Oxygen-Induced Retinal Vessel Loss and Suppresses Retinopathy in Mice

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