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ABSTRACT: Cell migration depends on cells being able to create and disassemble adhesive contacts. Hemidesmosomes are multiprotein structures that attach epithelia to basal lamina and disassemble during migration and carcinoma invasion. Phosphorylation of the β4 integrin, a hemidesmosome component, induces disassembly. Although kinases involved in β4 phosphorylation have been identified, little is known about phosphatases countering kinase action. Here we report that calcineurin, a serine-threonine protein phosphatase, regulates β4 phosphorylation. Calcineurin inhibitor cyclosporin A (CsA) and calcineurin-siRNA increase β4 phosphorylation, induce hemidesmosome disassembly, and increase migration in HaCat keratinocytes, suggesting that calcineurin negatively regulates β4 phosphorylation. We found no direct dephosphorylation of β4 by calcineurin or association between β4 and calcineurin, suggesting indirect regulation of β4 phosphorylation. We therefore assessed calcineurin influence on MAPK and PKC, known to phosphorylate β4. CsA increased MAPK activity, whereas MAPK inhibitors reduced CsA-induced β4 phosphorylation, suggesting that calcineurin restricts β4 phosphorylation by MAPK. Calcineurin is activated by calcium. Increased [Ca(2+)](i) reduces β4 phosphorylation and stabilizes hemidesmosomes, effects that are reversed by CsA, indicating that calcineurin mediates calcium effects on β4. However, MAPK activation is increased when [Ca(2+)](i) is increased, suggesting that calcineurin activates an additional mechanism that counteracts MAPK-induced β4 phosphorylation. Interestingly, in some squamous cell carcinoma cells, which have reduced hemidesmosomes and increased β4 phosphorylation, an increase in [Ca(2+)](i) using thapsigargin, bradykinin, or acetylcholine can increase hemidesmosomes and reduce β4 phosphorylation in a calcineurin-dependent manner. These findings have implications in calcineurin-inhibitor induced carcinoma, a complication of immunosuppressive therapy.
Journal of Biological Chemistry 08/2012; 287(39):32440-9. · 4.77 Impact Factor
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ABSTRACT: Hemidesmosomes (HDs) are multiprotein structures that anchor epithelia to the basement membrane. During squamous cell carcinoma (SCC) invasion, there is a reduction in the number of HDs, which may facilitate dissemination. Mechanisms of HD disassembly are incompletely understood. Previous work has shown that epidermal growth factor (EGF)-induced phosphorylation of the β4 integrin on three of its serines, S(1356)S(1360)S(1364), can induce HD disassembly in normal cells. Here, we examine the role of β4 integrin serine phosphorylation in SCC. We have found that around 60% of invasive cutaneous SCC show increased β4 phosphorylation on S(1356) when compared with carcinoma in situ or normal tissue. To assess the mechanisms by which SCC increases β4 phosphorylation, we performed in vitro analyses. Compared with keratinocytes, SCC cells showed increased levels of S(1356) phosphorylation in the absence of EGF, correlating with reduced HD-like structures. In addition, phospho-S(1356) signal was largely segregated from other HD components. Epidermal growth factor receptor and PKC inhibitors inhibited basal levels of S(1356) phosphorylation in SCC, suggesting that cells use intrinsic mechanisms to activate the EGF signaling pathway to induce β4 phosphorylation. Moreover, these inhibitors stabilized HD-like structures in SCC cells and reduced their migratory ability. Mutation of S(1356)S(1360)S(1364) in SCC cells to non-phosphorylatable alanines stabilized HD-like structures and substantially reduced migration, while mutation into phosphorylation mimicking aspartate reduced HD-like structures but had no effect on migration, suggesting that serine phosphorylation function is releasing anchorage rather than promoting migration. Altogether these results suggest that β4 serine phosphorylation may have an important role during SCC invasion by destabilizing HDs and facilitating migration.
Laboratory Investigation 07/2011; 91(10):1414-26. · 3.64 Impact Factor
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Shideh Kazerounian,
Mark Duquette,
Millys A Reyes,
James T Lawler,
Keli Song,
Carole Perruzzi,
Luca Primo,
Roya Khosravi-Far,
Federico Bussolino, Isaac Rabinovitz,
Jack Lawler
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ABSTRACT: CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation of the VEGFR-2 signaling pathway that requires Syk. Our findings also identify a role for Syk as a stimulator of VEGF-A-induced angiogenesis by increasing phosphorylation of Y1175 in VEGFR-2, which is a major tyrosine for promoting VEGF-A-induced endothelial cell migration. Together, these studies introduce a new signaling pathway for TSP-1, CD36, and Syk, and address the role of these proteins in regulating the angiogenic switch.
Blood 03/2011; 117(17):4658-66. · 9.90 Impact Factor
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ABSTRACT: Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A. We further demonstrate that 14-3-3, while not impeding the interaction between PP2A and FOXO3a, restrains its activity toward AKT phosphorylation sites T32/S253. Disruption of PP2A function revealed that after AKT inhibition, PP2A-mediated dephosphorylation of T32/S253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of FOXO3a. Our findings reveal that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation.
Molecular biology of the cell 03/2010; 21(6):1140-52. · 5.98 Impact Factor
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ABSTRACT: Hemidesmosomes (HDs) are multiprotein structures that anchor epithelial cells to the basement membrane. HD components include the alpha6beta4 integrin, plectin, and BPAGs (bullous pemphigoid antigens). HD disassembly in keratinocytes is necessary for cells to migrate and can be induced by EGF through beta4 integrin phosphorylation. We have identified a novel phosphorylation site on the beta4 integrin: S(1424). Preventing phosphorylation by mutating S-->A(1424) results in increased incorporation of beta4 into HDs and resistance to EGF-induced disassembly. In contrast, mutating S-->D(1424) (mimicking phosphorylation) partially mobilizes beta4 from HDs and potentiates the disassembly effects of other phosphorylation sites. In contrast to previously described sites that are phosphorylated upon growth factor stimulation, S(1424) already exhibits high constitutive phosphorylation, suggesting additional functions. Constitutive phosphorylation of S(1424) is distinctively enriched at the trailing edge of migrating keratinocytes where HDs are disassembled. Although most of this S(1424)-phosphorylated beta4 is found dissociated from HDs, a substantial amount can be associated with HDs near the cell margins, colocalizing with plectin but always excluding BPAGs, suggesting that phospho-S(1424) might be a mechanism to dissociate beta4 from BPAGs. S(1424) phosphorylation is PKC dependent. These data suggest an important role for S(1424) in the gradual disassembly of HDs induced by cell retraction.
Molecular biology of the cell 12/2008; 20(1):56-67. · 5.98 Impact Factor
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ABSTRACT: The phosphoinositide 3-kinase (PI 3-K) signaling axis is intimately associated with deregulated cancer cell growth, primarily by promoting increased survival through Akt/PKB (protein kinase B). However, there is relatively little information on the role of Akt in cancer cell motility, a key phenotype of invasive carcinomas. Here we report that activation of Akt inhibits carcinoma migration and invasion of breast cancer cells. Conversely, downregulation of Akt using RNA interference increased migration and invasion. Akt blunts invasion by inhibiting the transcriptional activity of NFAT (nuclear factor of activated T cells). Specifically, signaling through Akt reduces NFAT expression levels due to ubiquitination and proteasomal degradation, mediated by the E3 ubiquitin ligase HDM2. These results indicate that while Akt can promote tumor progression through increased cell survival mechanisms, it can block breast cancer cell motility and invasion by a mechanism that depends, at least in part, on the NFAT transcription factor.
Molecular Cell 12/2005; 20(4):539-50. · 14.18 Impact Factor
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ABSTRACT: Although the regulation of hemidesmosome dynamics during processes such as epithelial migration, wound healing, and carcinoma invasion is important, the mechanisms involved are poorly understood. The integrin alpha 6 beta 4 is an essential component of the hemidesmosome and a target of such regulation. Epidermal growth factor (EGF) can induce hemidesmosome disassembly by a mechanism that involves serine phosphorylation of the beta 4 integrin subunit. Using a combination of biochemical and mutational analyses, we demonstrate that EGF induces the phosphorylation of three specific serine residues (S(1356), S(1360), and S(1364)) located within the connecting segment of the beta 4 subunit and that phosphorylation on these residues accounts for the bulk of beta 4 phosphorylation stimulated by EGF. Importantly, phosphorylation of these serines is critical for the ability of EGF to disrupt hemidesmosomes. Using COS-7 cells, which assemble hemidesmosomes type II upon exogenous expression of the alpha 6 beta 4 integrin, we observed that expression of a beta 4 construct containing Ser-->Ala mutations of S(1356), S(1360), and S(1364) reduced the ability of EGF to disrupt hemidesmosomes and that this effect appears to involve cooperation among these phosphorylation sites. Moreover, expression of Ser-->Asp mutants that mimic constitutive phosphorylation reduced hemidesmosome formation. Protein kinase C-alpha (PKC-alpha) is the kinase responsible for phosphorylating at least two of these serines, based on in vitro kinase assays, peptide mapping, and mutational analysis. Together, these results highlight the importance of serine phosphorylation in regulating type II hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of beta 4, and argue for a key role for PKC-alpha in regulating these structures.
Molecular and Cellular Biology 06/2004; 24(10):4351-60. · 5.53 Impact Factor
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ABSTRACT: The Ras-mitogen-activated protein (Ras-MAP) kinase pathway regulates various cellular processes, including gene expression, cell proliferation, and survival. Ribosomal S6 kinase (RSK), a key player in this pathway, modulates the activities of several cytoplasmic and nuclear proteins via phosphorylation. Here we report the characterization of the cytoskeletal protein filamin A (FLNa) as a membrane-associated RSK target. We show that the N-terminal kinase domain of RSK phosphorylates FLNa on Ser(2152) in response to mitogens. Inhibition of MAP kinase signaling with UO126 or mutation of Ser(2152) to Ala on FLNa prevents epidermal growth factor (EGF)-stimulated phosphorylation of FLNa in vivo. Furthermore, phosphorylation of FLNa on Ser(2152) is significantly enhanced by the expression of wild-type RSK and antagonized by kinase-inactive RSK or specific reduction of endogenous RSK. Strikingly, EGF-induced, FLNa-dependent migration of human melanoma cells is significantly reduced by UO126 treatment. Together, these data provide substantial evidence that RSK phosphorylates FLNa on Ser(2152) in vivo. Given that phosphorylation of FLNa on Ser(2152) is required for Pak1-mediated membrane ruffling, our results suggest a novel role for RSK in the regulation of the actin cytoskeleton.
Molecular and Cellular Biology 05/2004; 24(7):3025-35. · 5.53 Impact Factor
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ABSTRACT: Blood vessel formation is a complex morphological process that is only beginning to be understood at the molecular level. In this study, we demonstrate a novel and critical role for the small GTPase, RhoB, in vascular development. RhoB null mice have retarded vascular development in the retina characterized by altered sprout morphology. Moreover, pharmaceutical means to deplete RhoB in neonatal rats is associated with apoptosis in the sprouting endothelial cells of newly forming vessels. Similarly, acute depletion of RhoB by antisense or dominant-negative strategies in primary endothelial cell culture models led to apoptosis and failures in tube formation. We identified a novel link between RhoB and the Akt survival signaling pathway to explain these changes. Confocal microscopy revealed that RhoB is highly localized to the nuclear margin with a small percentage found inside the nucleus. Similarly, total Akt is throughout the cell but has increased accumulation at the nuclear margin, and active phosphorylated Akt is found primarily inside the nucleoplasm, where it partially colocalizes with the RhoB therein. We show that this colocalization is functionally relevant, because when RhoB was depleted, Akt was excluded from the nucleus and total cellular Akt protein was decreased in a proteosome-dependent manner. Because the function of RhoB in vivo appears to only be rate limiting for endothelial cell sprouting, we propose that RhoB has a novel stage-specific function to regulate endothelial cell survival during vascular development. RhoB may offer a therapeutic target in diseases such as cancer, diabetic retinopathy, and macular degeneration, where the disruption of sprouting angiogenesis would be desirable.
Genes & Development 12/2003; 17(21):2721-32. · 11.66 Impact Factor
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ABSTRACT: The application of small interfering RNA (siRNA) oligonucleotides to silence gene expression has profound implications for
the intervention of human diseases including cancer. Using this technique, we explored the possibility that the α6β4 integrin,
a laminin adhesion receptor with a recognized role in the invasive phenotype of many carcinomas, represents a potential therapeutic
target to inhibit the migration and invasion of carcinoma cells. We found that siRNA oligonucleotides targeted to either subunit
of the α6β4 integrin reduced cell surface expression of this integrin and resulted in decreased invasion of MDA-MB-231 breast
carcinoma cells. Interestingly, reduced α6β4 expression also promoted decreased migration on non-laminin substrata indicating
that this integrin can function in a ligand-independent manner. In addition, the absence of β4 expression in these cells augmented
the formation of α6β1 heterodimers and increased adhesion to laminin-1. Taken together, these results substantiate the importance
of the α6β4 integrin in invasion and migration that has been demonstrated previously by expression of the β4 subunit in β4-deficient
cell lines and by function blocking antibodies. Furthermore, these data suggest that the utilization of siRNA oligonucleotides
to reduce the expression of the α6β4 integrin may be a useful approach to prevent carcinoma cell progression.
Clinical and Experimental Metastasis 09/2003; 20(6):569-576. · 3.52 Impact Factor
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ABSTRACT: The application of small interfering RNA (siRNA) oligonucleotides to silence gene expression has profound implications for the intervention of human diseases including cancer. Using this technique, we explored the possibility that the alpha6beta4 integrin, a laminin adhesion receptor with a recognized role in the invasive phenotype of many carcinomas, represents a potential therapeutic target to inhibit the migration and invasion of carcinoma cells. We found that siRNA oligonucleotides targeted to either subunit of the alpha6beta4 integrin reduced cell surface expression of this integrin and resulted in decreased invasion of MDA-MB-231 breast carcinoma cells. Interestingly, reduced alpha6beta4 expression also promoted decreased migration on non-laminin substrata indicating that this integrin can function in a ligand-independent manner. In addition, the absence of beta4 expression in these cells augmented the formation of alpha6beta1 heterodimers and increased adhesion to laminin-1. Taken together, these results substantiate the importance of the alpha6beta4 integrin in invasion and migration that has been demonstrated previously by expression of the beta4 subunit in beta4-deficient cell lines and by function blocking antibodies. Furthermore, these data suggest that the utilization of siRNA oligonucleotides to reduce the expression of the alpha6beta4 integrin may be a useful approach to prevent carcinoma cell progression.
Clinical and Experimental Metastasis 02/2003; 20(6):569-76. · 3.52 Impact Factor
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ABSTRACT: Although the involvement of α6β4, an integrin laminin receptor, in hemidesmosome organization has dominated the study of this integrin, recent studies are revealing novel functions for α6β4 in the migration of epithelial and carcinoma cells. The engagement of laminin by α6β4 can stabilize actin-rich protrusions and mediate traction forces necessary for cell movement. This integrin also has a significant impact on signaling molecules that stimulate migration and invasion, especially PI3-K and Rho GTPases. Activation of PI3-K by α6β4 enhances the formation of actin protrusions, and it may stimulate the function of other integrins, such as α3β1, that are also important for epithelial migration. Signaling through α6β4 may not always depend on the adhesive functions of this integrin, a possibility that has profound implications for migration and invasion because it implies that the ability of α6β4 to stimulate these processes is not limited to specific matrix environments.
Current Opinion in Cell Biology.
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ABSTRACT: The integrin family of adhesion receptors plays a major role in epithelial organization and function. Moreover, the altered expression and function of specific integrins most likely contributes significantly to carcinoma progression. The integrin alpha 6 beta 4, the focus of this review, is a receptor for several members of the laminin family and is preferentially expressed at the basal surface of most epithelia, where it contributes to basement membrane interactions. Mounting evidence suggests that the alpha 6 beta 4 integrin plays a key role in carcinoma cell biology. Several histopathological studies have established a correlation between alpha 6 beta 4 integrin expression and tumor progression. The importance of alpha 6 beta 4 expression in tumors in underscored by the findings that invading fronts of several carcinomas are enriched in the expression of alpha 6 beta 4 integrin ligands, such as laminin-1 and laminin-5. The participation of the alpha 6 beta 4 integrin in invasion is supported further by in vitro functional studies using carcinoma cells that have been transfected with the beta 4 cDNA. The mechanisms by which alpha 6 beta 4 contributes to tumor progression are probably related to its mechanical and signaling properties and are currently under intense study.
Arthur M. Mercurio.
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ABSTRACT: We demonstrate that the alpha6beta4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha6beta4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more PI3K activity than ligation of beta1 integrins, establishing specificity among integrins for PI3K activation. Alpha6beta4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha6beta4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.
Arthur M. Mercurio.
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ABSTRACT: Citation: Rabinovitz I, Mercurio AM. Dynamic functions of the alpha6beta4 integrin in carcinoma. In, “Cell Motility in Cancer Invasion and Metastasis”, Alan Wells (ed.) Springer. 2006. pp. 159-187. DOI: 10.1007/1-4020-4009-1_8 Summary: The α6β4 integrin plays pivotal but distinct roles in the biology of epithelial and carcinoma cells. In healthy epithelia, its major function is to anchor the epithelium to the basement membrane as a component of either Type I or Type II hemidesmosomes. The signaling capacity of this integrin in the hemidesmosome appears to be minimal. Epithelial wounds or, more importantly, factors linked to malignant transformation and progression can induce dramatic changes in the function of α6β4. In fact, a scenario is emerging of how the function of α6β4 is altered in carcinoma. Factors in the host-tumor microenvironment have the potential to mobilize α6β4 from hemidesmosomes and promote its association with F-actin. This association with F-actin enables this integrin to function in cell migration and to harness traction forces on laminin-containing matrices such as basement membranes, a process that could contribute to the remodeling of basement membranes during tumor invasion. Importantly, this altered localization of α6β4 appears to be coupled to an activation of its signaling potential. The primal signaling event triggered by α6β4 appears to be activation of PI3-K. Although the mechanism by which this occurs needs to be deciphered in more detail, especially with respect to the involvement of growth factor receptors, α6β4-mediated activation of PI3-K and its effectors such as Akt, mTOR and Rac has profound consequences on the biology of carcinoma cells. Arguably, the ability of α6β4 to stimulate the translation of VEGF and possibly other growth factors may be the most significant contribution of this integrin to cancer because of the potential autocrine and paracrine effects of these factors. Partial preview of chapter available via Google Books.
Arthur M. Mercurio.
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ABSTRACT: This review explores the mechanistic basis of carcinoma migration and invasion by focusing on the contribution of integrins. Integrins are essential for invasion not only for their ability to mediate physical interactions with extracellular matrices, but also for their ability to regulate signaling pathways that control actin dynamics and cell movement, as well as for growth and survival. Our comments center on a unique member of the integrin family, the alpha 6 beta 4 integrin, which is a receptor for the laminin family of basement membrane components. Numerous studies have implicated this integrin in the invasion of solid tumors and have provided a rationale for studying the mechanistic basis of its contribution to the invasive process. Such studies have revealed novel insights into the mechanism of carcinoma invasion that involve both the dynamics of cell migration and signaling pathways that regulate this migration.
Arthur M. Mercurio.
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[show abstract]
[hide abstract]
ABSTRACT: Although the involvement of alpha 6 beta 4, an integrin laminin receptor, in hemidesmosome organization has dominated the study of this integrin, recent studies are revealing novel functions for alpha 6 beta 4 in the migration of epithelial and carcinoma cells. The engagement of laminin by alpha 6 beta 4 can stabilize actin-rich protrusions and mediate traction forces necessary for cell movement. This integrin also has a significant impact on signaling molecules that stimulate migration and invasion, especially PI3-K and Rho GTPases. Activation of PI3-K by alpha 6 beta 4 enhances the formation of actin protrusions, and it may stimulate the function of other integrins, such as alpha 3 beta 1, that are also important for epithelial migration. Signaling through alpha 6 beta 4 may not always depend on the adhesive functions of this integrin, a possibility that has profound implications for migration and invasion because it implies that the ability of alpha 6 beta 4 to stimulate these processes is not limited to specific matrix environments.
Arthur M. Mercurio.
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ABSTRACT: Functional studies on the alpha6beta4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton. In this study, we examined the function of the alpha6beta4 integrin in clone A cells, a colon carcinoma cell line that expresses alpha6beta4 but no alpha6beta1 integrin and exhibits dynamic adhesion and motility on laminin-1. Time-lapse videomicroscopy of clone A cells on laminin-1 revealed that their migration is characterized by filopodial extension and stabilization followed by lamellae that extend in the direction of stabilized filopodia. A function-blocking mAb specific for the alpha6beta4 integrin inhibited clone A migration on laminin-1. This mAb also inhibited filopodial formation and stabilization and lamella formation. Indirect immunofluorescence microscopy revealed that the alpha6beta4 integrin is localized as discrete clusters in filopodia, lamellae, and retraction fibers. Although beta1 integrins were also localized in the same structures, a spatial separation of these two integrin populations was evident. In filopodia and lamellae, a striking colocalization of the alpha6beta4 integrin and F-actin was seen. An association between alpha6beta4 and F-actin is supported by the fact that alpha6beta4 integrin and actin were released from clone A cells by treatment with the F-actin- severing protein gelsolin and that alpha6beta4 immunostaining at the marginal edges of clone A cells on laminin-1 was resistant to solubilization with Triton X-100. Cytokeratins were not observed in filopodia and lamellipodia. Moreover, alpha6beta4 was extracted from these marginal edges with a Tween-40/deoxycholate buffer that solubilizes the actin cytoskeleton but not cytokeratins. Three other carcinoma cell lines (MIP-101, CCL-228, and MDA-MB-231) exhibited alpha6beta4 colocalized with actin in filopodia and lamellae. Formation of lamellae in these cells was inhibited with an alpha6-specific antibody. Together, these results indicate that the alpha6beta4 integrin functions in carcinoma migration on laminin-1 through its ability to promote the formation and stabilization of actin-containing motility structures.
Arthur M. Mercurio.
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ABSTRACT: We explored the hypothesis that the chemotactic migration of carcinoma cells that assemble hemidesmosomes involves the activation of a signaling pathway that releases the alpha6beta4 integrin from these stable adhesion complexes and promotes its association with F-actin in cell protrusions enabling it to function in migration. Squamous carcinoma-derived A431 cells were used because they express alpha6beta4 and migrate in response to EGF stimulation. Using function-blocking antibodies, we show that the alpha6beta4 integrin participates in EGF-stimulated chemotaxis and is required for lamellae formation on laminin-1. At concentrations of EGF that stimulate A431 chemotaxis ( approximately 1 ng/ml), the alpha6beta4 integrin is mobilized from hemidesmosomes as evidenced by indirect immunofluorescence microscopy using mAbs specific for this integrin and hemidesmosomal components and its loss from a cytokeratin fraction obtained by detergent extraction. EGF stimulation also increased the formation of lamellipodia and membrane ruffles that contained alpha6beta4 in association with F-actin. Importantly, we demonstrate that this mobilization of alpha6beta4 from hemidesmosomes and its redistribution to cell protrusions occurs by a mechanism that involves activation of protein kinase C-alpha and that it is associated with the phosphorylation of the beta4 integrin subunit on serine residues. Thus, the chemotactic migration of A431 cells on laminin-1 requires not only the formation of F-actin-rich cell protrusions that mediate alpha6beta4-dependent cell movement but also the disruption of alpha6beta4-containing hemidesmosomes by protein kinase C.
Arthur M. Mercurio.
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[show abstract]
[hide abstract]
ABSTRACT: This review explores the mechanistic basis of carcinoma migration and invasion by focusing on the contribution of integrins. Integrins are essential for invasion not only for their ability to mediate physical interactions with extracellular matrices, but also for their ability to regulate signaling pathways that control actin dynamics and cell movement, as well as for growth and survival. Our comments center on a unique member of the integrin family, the α 6β 4 integrin, which is a receptor for the laminin family of basement membrane components. Numerous studies have implicated this integrin in the invasion of solid tumors and have provided a rationale for studying the mechanistic basis of its contribution to the invasive process. Such studies have revealed novel insights into the mechanism of carcinoma invasion that involve both the dynamics of cell migration and signaling pathways that regulate this migration.
Seminars in Cancer Biology.
