Focal adhesion kinase-dependent focal adhesion recruitment of SH2 domains directs SRC into focal adhesions to regulate cell adhesion and migration

Migration and proliferation of cardiac fibroblasts (CFs) play an important role in the myocardial remodeling process. While many factors have been identified that regulate CF growth and migration, less is known about the signaling mechanisms involved in these processes. Here, we utilized Cre-LoxP technology to obtain focal adhesion kinase (FAK)-deficient adult mouse CFs and studied how FAK functioned in modulating cell adhesion, proliferation, and migration of these cells. Treatment of FAKflox/flox CFs with Ad/Cre virus caused over 70% reduction of FAK protein levels within a cell population. FAK-deficient CFs showed no changes in focal adhesions, cell morphology, or protein expression levels of vinculin, talin, or paxillin; proline-rich tyrosine kinase 2 (Pyk2) expression and activity were increased. Knockdown of FAK protein in CFs increased PDGF-BB-induced proliferation, while it reduced PDGF-BB-induced migration. Adhesion to fibronectin was not altered. To distinguish between the function of FAK and Pyk2, FAK function was inhibited via adenoviral-mediated overexpression of the natural FAK inhibitor FAK-related nonkinase (FRNK). Ad/FRNK had no effect on Pyk2 expression, inhibited the PDGF-BB-induced migration, but did not change the PDGF-BB-induced proliferation. FAK deficiency had only modest effects on increasing PDGF-BB activation of p38 and JNK MAPKs, with no alteration in the ERK response vs. control cells. These results demonstrate that FAK is required for the PDGF-BB-induced migratory response of adult mouse CFs and suggest that FAK could play an essential role in the wound-healing response that occurs in numerous cardiac pathologies.

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Contractility modulates cell adhesion strengthening through focal adhesion kinase and assembly of vinculin-containing focal adhesions

Journal of Cellular Physiology ◽

10.1002/jcp.22084 ◽

2010 ◽

pp. n/a-n/a ◽

Cited By ~ 14

Author(s):

David W. Dumbauld ◽

Heungsoo Shin ◽

Nathan D. Gallant ◽

Kristin E. Michael ◽

Harish Radhakrishna ◽

...

Keyword(s):

Cell Adhesion ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Focal Adhesions

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Identification of a bipartite focal adhesion localization signal in RhoU/Wrch-1, a Rho family GTPase that regulates cell adhesion and migration

Biology of the Cell ◽

10.1042/bc20070058 ◽

2007 ◽

Vol 99 (12) ◽

pp. 701-716 ◽

Cited By ~ 43

Author(s):

Stéphane Ory ◽

Hélène Brazier ◽

Anne Blangy

Keyword(s):

Cell Adhesion ◽

Focal Adhesion ◽

Cell Adhesion And Migration ◽

Localization Signal ◽

Rho Family ◽

And Migration

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Hematopoietic PBX-interacting protein (HPIP) is over expressed in breast infiltrative ductal carcinoma and regulates cell adhesion and migration through modulation of focal adhesion dynamics

Oncogene ◽

10.1038/onc.2014.389 ◽

2014 ◽

Vol 34 (35) ◽

pp. 4601-4612 ◽

Cited By ~ 12

Author(s):

S Bugide ◽

D David ◽

A Nair ◽

N Kannan ◽

V S K Samanthapudi ◽

...

Keyword(s):

Cell Adhesion ◽

Focal Adhesion ◽

Ductal Carcinoma ◽

Interacting Protein ◽

Infiltrative Ductal Carcinoma ◽

Cell Adhesion And Migration ◽

And Migration

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Guiding cell adhesion and motility by modulating cross-linking and topographic properties of microgel arrays

PLoS ONE ◽

10.1371/journal.pone.0257495 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257495

Author(s):

Janine Riegert ◽

Alexander Töpel ◽

Jana Schieren ◽

Renee Coryn ◽

Stella Dibenedetto ◽

...

Keyword(s):

Tissue Engineering ◽

Cell Migration ◽

Cell Adhesion ◽

Focal Adhesion ◽

Sertoli Cells ◽

Cellular Systems ◽

Cross Linking ◽

Cell Adhesion And Migration ◽

And Migration ◽

The Impact

Biomaterial-driven modulation of cell adhesion and migration is a challenging aspect of tissue engineering. Here, we investigated the impact of surface-bound microgel arrays with variable geometry and adjustable cross-linking properties on cell adhesion and migration. We show that cell migration is inversely correlated with microgel array spacing, whereas directionality increases as array spacing increases. Focal adhesion dynamics is also modulated by microgel topography resulting in less dynamic focal adhesions on surface-bound microgels. Microgels also modulate the motility and adhesion of Sertoli cells used as a model for cell migration and adhesion. Both focal adhesion dynamics and speed are reduced on microgels. Interestingly, Gas2L1, a component of the cytoskeleton that mediates the interaction between microtubules and microfilaments, is dispensable for the regulation of cell adhesion and migration on microgels. Finally, increasing microgel cross-linking causes a clear reduction of focal adhesion turnover in Sertoli cells. These findings not only show that spacing and rigidity of surface-grafted microgels arrays can be effectively used to modulate cell adhesion and motility of diverse cellular systems, but they also form the basis for future developments in the fields of medicine and tissue engineering.

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PAK4 methylation by the methyltransferase SETD6 attenuates cell adhesion

Scientific Reports ◽

10.1038/s41598-020-74081-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Zlata Vershinin ◽

Michal Feldman ◽

Dan Levy

Keyword(s):

Cell Adhesion ◽

Mammalian Cells ◽

Focal Adhesions ◽

Vital Role ◽

Migration And Invasion ◽

Wild Type ◽

Set Domain ◽

Cell Adhesion And Migration ◽

P21 Activated Kinase ◽

And Migration

Abstract P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts with and methylates PAK4 at chromatin in mammalian cells, leading to activation of the Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion. Specific methylation of PAK4 at K473 also attenuates paxillin localization to focal adhesions leading to overall reduction in adhesion-related features, such as filopodia and actin structures. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migrative and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the regulation of cell adhesion and migration.

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Focal adhesion kinase signaling is decreased in polyamine-depleted IEC-6 cells

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.2.c475 ◽

2001 ◽

Vol 281 (2) ◽

pp. C475-C485 ◽

Cited By ~ 22

Author(s):

Ramesh M. Ray ◽

Mary Jane Viar ◽

Shirley A. McCormack ◽

Leonard R. Johnson

Keyword(s):

Extracellular Matrix ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Focal Adhesions ◽

Stress Fiber ◽

Fiber Formation ◽

Integrin Signaling ◽

Actin Stress Fiber ◽

Stress Fiber Formation ◽

And Migration

Polyamines are essential to the migration of epithelial cells in the intestinal mucosa. Cells depleted of polyamines do not attach as rapidly to the extracellular matrix and do not form the actin stress fibers essential for migration. Because both attachment and stress fiber formation depend on integrin signaling and the formation of focal adhesions, we examined these and related processes in polyamine-depleted IEC-6 cells. There was general decreased tyrosine phosphorylation of focal adhesion kinase (FAK), and, specifically, decreased phosphorylation of Tyr-925, the paxillin binding site. In control cells, FAK phosphorylation was rapid after attachment to the extracellular matrix, while attached cells depleted of polyamines had significantly delayed phosphorylation. FAK activity was also significantly inhibited in polyamine-depleted cells as was the phosphorylation of paxillin. Polyamine-depleted cells failed to spread normally after attachment, and immunocytochemistry showed little colocalization of FAK and actin compared with controls. Focal adhesion complex formation was greatly reduced in the absence of polyamines. These data suggest that defective integrin signaling may, at least in part, account for the decreased rates of attachment, actin stress fiber formation, spreading, and migration observed in polyamine-depleted cells.

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