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Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling.

ABSTRACT: We previously showed that the cell-cell junction protein plakoglobin (PG) not only suppresses motility of keratinocytes in contact with each other, but also, unexpectedly, of single cells. Here we show that PG deficiency results in extracellular matrix (ECM)-dependent disruption of mature focal adhesions and cortical actin organization. Plating PG?/? cells onto ECM deposited by PG+/? cells partially restored normal cell morphology and inhibited PG?/? cell motility. In over 70 adhesion molecules whose expression we previously showed to be altered in PG?/? cells, a substantial decrease in fibronectin (FN) in PG?/? cells stood out. Re-introduction of PG into PG?/? cells restored FN expression, and keratinocyte motility was reversed by plating PG?/? cells onto FN. Somewhat surprisingly, based on previously reported roles for PG in regulating gene transcription, PG-null cells exhibited an increase, not a decrease, in FN promoter activity. Instead, PG was required for maintenance of FN mRNA stability. PG?/? cells exhibited an increase in activated Src, one of the kinases controlled by FN, a phenotype reversed by plating PG?/? cells on ECM deposited by PG+/? keratinocytes. PG?/? cells also exhibited Src-independent activation of the small GTPases Rac1 and RhoA. Both Src and RhoA inhibition attenuated PG?/? keratinocyte motility. We propose a novel role for PG in regulating cell motility through distinct ECM-Src and RhoGTPase-dependent pathways, influenced in part by PG-dependent regulation of FN mRNA stability.

SUBMITTER: Todorovic V

PROVIDER: S-EPMC2951470 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling.

Todorović Viktor V Desai Bhushan V BV Patterson Melanie J Schroeder MJ Amargo Evangeline V EV Dubash Adi D AD Yin Taofei T Jones Jonathan C R JC Green Kathleen J KJ

Journal of cell science 20100928 Pt 20

We previously showed that the cell-cell junction protein plakoglobin (PG) not only suppresses motility of keratinocytes in contact with each other, but also, unexpectedly, of single cells. Here we show that PG deficiency results in extracellular matrix (ECM)-dependent disruption of mature focal adhesions and cortical actin organization. Plating PG⁻/⁻ cells onto ECM deposited by PG+/⁻ cells partially restored normal cell morphology and inhibited PG⁻/⁻ cell motility. In over 70 adhesion molecules ...[more]

PMID: 20876660

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Project description:Smooth muscle cells are maintained in a differentiated state in the vessel wall, but can be modulated to a synthetic phenotype following injury. Smooth muscle phenotypic modulation is thought to play an important role in the pathology of vascular occlusive diseases. Phenotypically modulated smooth muscle cells exhibit increased proliferative and migratory properties that accompany the downregulation of smooth muscle cell marker proteins. Extracellular matrix proteins, including fibronectin, can regulate the smooth muscle phenotype when used as adhesive substrates. However, cells produce and organize a 3-dimensional fibrillar extracellular matrix, which can affect cell behavior in distinct ways from the protomeric 2-dimensional matrix proteins that are used as adhesive substrates. We previously showed that the deposition/polymerization of fibronectin into the extracellular matrix can regulate the deposition and organization of other extracellular matrix molecules in vitro. Further, our published data show that the presence of a fibronectin polymerization inhibitor results in increased expression of smooth muscle cell differentiation proteins and inhibits vascular remodeling in vivo. In this manuscript, we used an in vitro cell culture system to determine the mechanism by which fibronectin polymerization affects smooth muscle phenotypic modulation. Our data show that fibronectin polymerization decreases the mRNA levels of multiple smooth muscle differentiation genes, and downregulates the levels of smooth muscle ?-actin and calponin proteins by a Rac1-dependent mechanism. The expression of smooth muscle genes is transcriptionally regulated by fibronectin polymerization, as evidenced by the increased activity of luciferase reporter constructs in the presence of a fibronectin polymerization inhibitor. Fibronectin polymerization also promotes smooth muscle cell growth, and decreases the levels of actin stress fibers. These data define a Rac1-dependent pathway wherein fibronectin polymerization promotes the SMC synthetic phenotype by modulating the expression of smooth muscle cell differentiation proteins.

Dataset Information

Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling.

Publications

Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling.

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