Faculty Opinions recommendation of Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells.

2011 ◽  
Author(s):  
Ron Prywes
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase A ◽  
Migrating Cells

scholarly journals Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells

2008 ◽  
Vol 19 (11) ◽  
pp. 4930-4941 ◽  
Author(s):  
Chinten J. Lim ◽  
Kristin H. Kain ◽  
Eugene Tkachenko ◽  
Lawrence E. Goldfinger ◽  
Edgar Gutierrez ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Leading Edge ◽  
Pi3 Kinase ◽  
Early Event ◽  
Type I ◽  
Cell Protrusion ◽  
Kinase A ◽  
Migrating Cells

cAMP-dependent protein kinase A (PKA) is important in processes requiring localized cell protrusion, such as cell migration and axonal path finding. Here, we used a membrane-targeted PKA biosensor to reveal activation of PKA at the leading edge of migrating cells. Previous studies show that PKA activity promotes protrusion and efficient cell migration. In live migrating cells, membrane-associated PKA activity was highest at the leading edge and required ligation of integrins such as α4β1 or α5β1 and an intact actin cytoskeleton. α4 integrins are type I PKA-specific A-kinase anchoring proteins, and we now find that type I PKA is important for localization of α4β1 integrin-mediated PKA activation at the leading edge. Accumulation of 3′ phosphorylated phosphoinositides [PtdIns(3,4,5)P3] products of phosphatidylinositol 3-kinase (PI3-kinase) is an early event in establishing the directionality of migration; however, polarized PKA activation did not require PI3-kinase activity. Conversely, inhibition of PKA blocked accumulation of a PtdIns(3,4,5)P3-binding protein, the AKT-pleckstrin homology (PH) domain, at the leading edge; hence, PKA is involved in maintaining cell polarity during migration. In sum, we have visualized compartment-specific PKA activation in migrating cells and used it to reveal that adhesion-mediated localized activation of PKA is an early step in directional cell migration.

scholarly journals Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis

2018 ◽  
Author(s):  
Andrew J. McKenzie ◽  
Tamara F. Williams ◽  
Kathryn V. Svec ◽  
Alan K. Howe
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Rho Kinase ◽  
Mechanical Stretch ◽  
Cell Types ◽  
Dependent Manner ◽  
Actomyosin Contractility ◽  
Kinase A ◽  
Migrating Cells

AbstractDynamic subcellular regulation of Protein kinase A (PKA) activity is important for the motile behavior of many cell types, yet the mechanisms governing PKA activity during cell migration remain largely unknown. The motility of SKOV-3 epithelial ovarian cancer (EOC) cells has been shown to be dependent on both localized PKA activity and, more recently, on mechanical reciprocity between cellular tension and extracellular matrix (ECM) rigidity. Here, we investigated the possibility that PKA is regulated by mechanical signaling during migration. We find that localized PKA activity in migrating cells rapidly decreases upon inhibition of actomyosin contractility (specifically, of myosin ATPase, ROCK (Rho kinase), or MLCK (myosin light chain kinase) activity). Moreover, PKA activity is spatially and temporally correlated with cellular traction forces in migrating cells. Additionally, PKA is rapidly and locally activated by mechanical stretch in an actomyosin contractility-dependent manner. Finally, inhibition of PKA activity inhibits mechanically-guided migration, also known as durotaxis. These observations establish PKA as a locally-regulated effector of cellular mechanotransduction and as a regulator of mechanically-guided cell migration.

scholarly journals Spatial restriction of α4 integrin phosphorylation regulates lamellipodial stability and α4β1-dependent cell migration

2003 ◽  
Vol 162 (4) ◽  
pp. 731-741 ◽  
Author(s):  
Lawrence E. Goldfinger ◽  
Jaewon Han ◽  
William B. Kiosses ◽  
Alan K. Howe ◽  
Mark H. Ginsberg
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Control Cell ◽  
Adaptor Protein ◽  
Leading Edge ◽  
Dependent Cell ◽  
Kinase A ◽  
Migrating Cells

Întegrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from α4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient α4-mediated migration requires spatial control of α4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated α4 accumulated along the leading edge. Blocking α4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced α4-dependent migration and lamellipodial stability. α4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-α4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated α4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with α4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.

scholarly journals Protein kinase A governs a RhoA–RhoGDI protrusion–retraction pacemaker in migrating cells

2011 ◽  
Vol 13 (6) ◽  
pp. 660-667 ◽  
Author(s):  
Eugene Tkachenko ◽  
Mohsen Sabouri-Ghomi ◽  
Olivier Pertz ◽  
Chungho Kim ◽  
Edgar Gutierrez ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase A ◽  
Migrating Cells

scholarly journals Protein kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis

2020 ◽  
Vol 31 (1) ◽  
pp. 45-58 ◽  
Author(s):  
Andrew J. McKenzie ◽  
Kathryn V. Svec ◽  
Tamara F. Williams ◽  
Alan K. Howe
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mechanical Stimulation ◽  
Traction Forces ◽  
Cell Matrix ◽  
Actomyosin Contractility ◽  
Cellular Mechanotransduction ◽  
Kinase A ◽  
Migrating Cells

Here, we show that localized PKA activity in migrating cells is regulated by cell–matrix tension, correlates with cellular traction forces, is enhanced by acute mechanical stimulation, and is required for durotaxis. This establishes PKA as an effector of cellular mechanotransduction and as a regulator of mechanically guided cell migration.

Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽  
2000 ◽  
pp. 377-383 ◽  
Author(s):  
L Leonardsen ◽  
A Wiersma ◽  
M Baltsen ◽  
AG Byskov ◽  
CY Andersen
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Mouse Oocytes ◽  
Mitogen Activated Protein ◽  
Dependent Signal ◽  
Kinase Pathway ◽  
Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

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