Second Generation Monoclonal Antibodies to the Human Integrin α<sup>6</sup>β<sub>4</sub>

Kennel, Stephen J.; Epler, R.G.; Lankford, Trish K.; Foote, Linda J.; Dickas, V.; Canamucio, M.; Cavalierie, R.; Cosimelli, Maurizio; Venturo, Irene; Falcioni, Rita; Sacchi, Ada

doi:10.1089/hyb.1990.9.243

Cited by 62 publications

(38 citation statements)

References 17 publications

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“…Antibodies and matrix proteins. The anti-h 4 antibodies (439-9B and 450-11A) and the anti-ErbB-2 (W6/100) were prepared as described (15,25). The anti-ErbB-2 antibody (clone 3B5) used in Western blot experiment was from Transduction Laboratories (Lexington, KY).…”

Section: Methodsmentioning

confidence: 99%

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Bon¹,

Folgiero²,

Bossi³

et al. 2006

Clinical Cancer Research

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Purpose: The a 6 h 4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the h 4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ ErbB-2^transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous h 4 integrin subunit expression. Experimental Design: In vitro and in vivo tumor growth and the biochemical consequences of h 4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach. Results: Our data show that tumor growth of mammary tumor cells strictly depends on h 4 expression, confirming the relevance of h 4 protein in these cells. Moreover, interference with h 4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether h 4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous h 4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c^mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 h 4^s hort hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment. Conclusions: Overall, these results confirm the relevance of h 4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.

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Section: Methodsmentioning

confidence: 99%

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Bon¹,

Folgiero²,

Bossi³

et al. 2006

Clinical Cancer Research

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“…Antibodies directed against integrin subunits were the rat monoclonal antibody (mAb) GoH3 to a6 (Sonnenberg et al, 1987); the mouse anti-a6 mAb 450-33D (Kennel et al, 1990), kindly provided by Dr. S.J. Kennel (Oak Ridge National Laboratory, Oak Ridge, TN); the rabbit polyclonal antibody directed against the carboxy-terminal sequence of a6A (Delwel et al, 1993); the mouse mAb lAlO to the cytoplasmic domain of a6A .…”

Section: Materials and Methods Cell Culture Antibodies And Matrix Pmentioning

confidence: 99%

Distinct and overlapping ligand specificities of the alpha 3A beta 1 and alpha 6A beta 1 integrins: recognition of laminin isoforms.

Delwel

Melker

Hogervorst

et al. 1994

MBoC

205

145

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The ligand specificity of the a3A31 integrin was analyzed using K562 cells transfected with full-length a3A cDNA and was compared with that of a6A31 in similarly transfected K562 cells. Clones were obtained that showed comparable surface expression of either a3A31 or a6A31 integrins. Those expressing a3A,31 attached to and spread on immunopurified human kalinin and cellular matrices containing human kalinin, which is a particular isoform of laminin. In addition, a3A transfectants adhered to bovine kidney laminins possessing a novel A chain variant. Binding to kalinin was blocked by a monoclonal antibody against the A chain constituent of kalinin and adhesion to both kalinin and kidney laminins by anti-a3 and 31 monoclonal antibodies. The a3A transfected cells bound more strongly to kalinin and bovine kidney laminins after treatment with the 31 stimulatory antibody TS2/16. A distinctly weaker and activation-dependent adhesion of a3A transfectants was observed on human placental laminins possessing the Am chain variant (merosin), and no adhesion occurred on bovine heart laminins and murine EHS tumor laminin. Further inactive substrates were fibronectin, nidogen, and collagen types IV and VI, indicating that the a3Afl integrin is a much less promiscuous receptor than thought before. By contrast, a6A transfected cells adhered to all laminin isoforms when stimulated with TS2/16. Adhesion also occurred only on bovine kidney laminins in the absence of TS2/16. These results demonstrate that both a3A31 and a6A#l integrins are typical laminin receptors but that their affinity and activation dependence for binding to various laminin isoforms differ considerably.

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“…The hybridoma producing the mouse anti-pl activating mAb TS2/16 [46] was purchased from American Type Culture Collection. The mouse mAbs 450-1 OD and 450-9D, directed against intracellular and extracellular epitopes on p4, respectively [47], were kind gifts of Dr S. J. Kennel (Oak Ridge National Laboratory, Oak Ridge TN). The mouse anti-p4 mAb 4.3E1 [48] was generously provided by Dr E. Engvall (La Jolla Cancer Research Foundation, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

The Role of the Cytoplasmic Domain of α6 Integrin in the Assembly and Function of α6β1 and α6β4

Melker

Sonnenberg

1996

European Journal of Biochemistry

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We have studied the role of the cytoplasmic domain of a6 in the assembly and function of the a6/j'4 integrin, and compared it with the role of a6 in the assembly and function of a6/jl, by transfection of cDNAs encoding cytoplasmic mutants of (16 into K562 cells with or without full-length p4 cDNA. Des-(1 022-1050)-a6, which contains a deletion C-terminal to the GFFKR motif, was expressed in association with PI, but associated preferentially with p4, whereas the wild-type a6 subunit associated efficiently with pl and 114. Des-(1016-1050)-a6, which lacked also the GFFKR sequence, was only expressed at the cell surface when p4 was available. Transient expression in COS-7 cells showed that des-(1016-1OSO)-cx6 was retained in the endoplasmic reticulum as a monomer, which suggests that truncation of the cytoplasmic domain reduces the affinity of a6 for 81, particularly when the GFFKR sequence is absent.Although the GFFKR motif is not essential for association of a6 with p4, it increases the stability of the a6P4 integrin. The cytoplasmic domain of a6 is essential for inside-out and outside-in signaling via the a6p1 receptor, but not for adhesion via a6P4. We show that a6p4 is a constitutively active receptor. Thus, unlike adhesion by most other integrins, adhesion by a6p4 does not seem to depend on any active cellular process. Binding of u6p4 to ligand was only slightly affected by truncation of the a6 cytoplasmic domain N-terminal to the GFFKR sequence and became partially dependent on metabolic energy. These data indicate that truncations of the cytoplasmic domain of the a6 subunit affect the assembly and function of a6pl more strongly than those of a6p4. This difference may be due to the greater affinity of a6 for p4 than for 81, which makes m6P4 less susceptible to the effect of truncations.

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Second Generation Monoclonal Antibodies to the Human Integrin α⁶β₄

Cited by 62 publications

References 17 publications

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Distinct and overlapping ligand specificities of the alpha 3A beta 1 and alpha 6A beta 1 integrins: recognition of laminin isoforms.

The Role of the Cytoplasmic Domain of α6 Integrin in the Assembly and Function of α6β1 and α6β4

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Second Generation Monoclonal Antibodies to the Human Integrin α6β4

Cited by 62 publications

References 17 publications

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Distinct and overlapping ligand specificities of the alpha 3A beta 1 and alpha 6A beta 1 integrins: recognition of laminin isoforms.

The Role of the Cytoplasmic Domain of α6 Integrin in the Assembly and Function of α6β1 and α6β4

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Product

Resources

About

Second Generation Monoclonal Antibodies to the Human Integrin α⁶β₄