Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells
Rabinovitz, Isaac ; Toker, Alex ; Mercurio, Arthur M.
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UMass Chan Affiliations
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Keywords
Antigens, Surface
Carbazoles
Carcinoma, Squamous Cell
Cell Membrane
Cell Size
*Chemotaxis
Desmosomes
Enzyme Activation
Epidermal Growth Factor
Humans
Indoles
Integrin alpha6beta4
Integrins
Keratins
Laminin
Phosphorylation
Phosphoserine
Phosphotyrosine
Protein Kinase C
Pseudopodia
Receptor, Epidermal Growth Factor
Signal Transduction
Tumor Cells, Cultured
Cancer Biology
Neoplasms
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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.
Source
J Cell Biol. 1999 Sep 6;146(5):1147-60. Link to article on publisher's website