scholarly journals Daydreamer, a Ras effector and GSK-3 substrate, is important for directional sensing and cell motility

2013 ◽  
Vol 24 (2) ◽  
pp. 100-114 ◽  
Author(s):  
Verena Kölsch ◽  
Zhouxin Shen ◽  
Susan Lee ◽  
Katarzyna Plak ◽  
Pouya Lotfi ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Leading Edge ◽  
Adaptor Proteins ◽  
Cell Polarization ◽  
Glycogen Synthase Kinase 3 ◽  
Dynamic Regulation ◽  
Multiple Substrates ◽  
Directional Movement ◽  
Phosphoinositide 3 Kinase ◽  
Kinetics Of

How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA− cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA− cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA− cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.

scholarly journals GSK3 as a Regulator of Cytoskeleton Architecture: Consequences for Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2092
Author(s):  
Daria Hajka ◽  
Bartosz Budziak ◽  
Łukasz Pietras ◽  
Przemysław Duda ◽  
James A. McCubrey ◽  
...  
Keyword(s):  
Growth And Development ◽  
Glycogen Synthase ◽  
Vital Role ◽  
Cell Polarization ◽  
Glycogen Synthase Kinase 3 ◽  
Directional Migration ◽  
Cellular Physiology ◽  
A Cell ◽  
Health And Disease ◽  
Migration Of Cells

Glycogen synthase kinase 3 (GSK3) was initially isolated as a critical protein in energy metabolism. However, subsequent studies indicate that GSK-3 is a multi-tasking kinase that links numerous signaling pathways in a cell and plays a vital role in the regulation of many aspects of cellular physiology. As a regulator of actin and tubulin cytoskeleton, GSK3 influences processes of cell polarization, interaction with the extracellular matrix, and directional migration of cells and their organelles during the growth and development of an animal organism. In this review, the roles of GSK3–cytoskeleton interactions in brain development and pathology, migration of healthy and cancer cells, and in cellular trafficking of mitochondria will be discussed.

scholarly journals Type Iγ PIP Kinase Is a Novel Uropod Component that Regulates Rear Retraction during Neutrophil Chemotaxis

2007 ◽  
Vol 18 (12) ◽  
pp. 5069-5080 ◽  
Author(s):  
Mary A. Lokuta ◽  
Melissa A. Senetar ◽  
David A. Bennin ◽  
Paul A. Nuzzi ◽  
Keefe T. Chan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Leading Edge ◽  
Time Lapse ◽  
Cell Polarization ◽  
Neutrophil Chemotaxis ◽  
Directed Migration ◽  
Time Lapse Microscopy ◽  
Phosphatidylinositol Phosphate ◽  
Phosphoinositide 3 Kinase ◽  
Made In

Cell polarization is necessary for directed migration and leukocyte recruitment to inflamed tissues. Recent progress has been made in defining the molecular mechanisms that regulate chemoattractant-induced cell polarity during chemotaxis, including the contribution of phosphoinositide 3-kinase (PI3K)-dependent phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] synthesis at the leading edge. However, less is known about the molecular composition of the cell rear and how the uropod functions during cell motility. Here, we demonstrate that phosphatidylinositol phosphate kinase type Iγ (PIPKIγ661), which generates PtdIns(4,5)P2, is enriched in the uropod during chemotaxis of primary neutrophils and differentiated HL-60 cells (dHL-60). Using time-lapse microscopy, we show that enrichment of PIPKIγ661 at the cell rear occurs early upon chemoattractant stimulation and is persistent during chemotaxis. Accordingly, we were able to detect enrichment of PtdIns(4,5)P2at the uropod during chemotaxis. Overexpression of kinase-dead PIPKIγ661 compromised uropod formation and rear retraction similar to inhibition of ROCK signaling, suggesting that PtdIns(4,5)P2synthesis is important to elicit the backness response during chemotaxis. Together, our findings identify a previously unknown function for PIPKIγ661 as a novel component of the backness signal that regulates rear retraction during chemotaxis.

scholarly journals The phosphoinositide 3-kinase pathway and glycogen synthase kinase-3 positively regulate the activity of metal-responsive transcription factor-1 in response to zinc ions

2018 ◽  
Vol 96 (6) ◽  
pp. 726-733 ◽  
Author(s):  
Yannick Andéol ◽  
Jessica Bonneau ◽  
Laurence M. Gagné ◽  
Kevin Jacquet ◽  
Véronique Rivest ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glycogen Synthase ◽  
Transition Metal Ions ◽  
Pi3k Pathway ◽  
Glycogen Synthase Kinase ◽  
Hek293 Cells ◽  
Glycogen Synthase Kinase 3 ◽  
Zinc Ions ◽  
Phosphoinositide 3 Kinase ◽  
Transcription Factor 1

Metal-responsive transcription factor-1 (MTF-1) is a metal-regulatory transcription factor essential for induction of the genes encoding metallothioneins (MTs) in response to transition metal ions. Activation of MTF-1 is dependent on the interaction of zinc with the zinc fingers of the protein. In addition, phosphorylation is essential for MTF-1 transactivation. We previously showed that inhibition of phosphoinositide 3-kinase (PI3K) abrogated Mt expression and metal-induced MTF-1 activation in human hepatocellular carcinoma (HCC) HepG2 and mouse L cells, thus showing that the PI3K signaling pathway positively regulates MTF-1 activity and Mt gene expression. However, it has also been reported that inhibition of PI3K has no significant effects on Mt expression in immortalized epithelial cells and increases Mt expression in HCC cells. To further characterize the role of the PI3K pathway on the activity of MTF-1, transfection experiments were performed in HEK293 and HepG2 cells in presence of glycogen synthase kinase-3 (GSK-3), mTOR–C1, and mTOR–C2 inhibitors, as well as of siRNAs targeting Phosphatase and TENsin homolog (PTEN). We showed that inhibition of the mTOR–C2 complex inhibits the activity of MTF-1 in HepG2 and HEK293 cells, while inhibition of the mTOR–C1 complex or of PTEN stimulates MTF-1 activity in HEK293 cells. These results confirm that the PI3K pathway positively regulates MTF-1 activity. Finally, we showed that GSK-3 is required for MTF-1 activation in response to zinc ions.

scholarly journals Glycogen synthase kinase 3 (GSK-3) controls T-cell motility andinteractions with antigen presenting cells

2020 ◽  
Author(s):  
Alison Taylor ◽  
Christopher E. Rudd
Keyword(s):  
T Cell ◽  
Cell Motility ◽  
Glycogen Synthase ◽  
Antigen Presenting Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Negative Effects ◽  
Serine Kinase ◽  
Multiple Substrates ◽  
Antigen Presenting

Abstract Objective: The threonine/serine kinase glycogen synthase kinase 3 (GSK-3) targets multiple substrates in T-cells and regulates the expression of Tbet and PD-1. However, it has been unclear whether GSK-3 has any effect on T-cell motility or their interactions with antigen presenting cells. Results: Here, we show that GSK-3 controls T-cell motilityand interactions with other cells. Inhibition of GSK-3, using structurally distinct inhibitors, reduced T-cell motility in terms of speed and distance travelled. Furthermore, SB415286 reduced the number of cell to cell contacts, however the duration of these established contacts with other cells did not differ in the presence of SB415286. This inhibition of motility did not affect the ability of GSK-3 inhibitors to enhance cytolytic T-cell (CTL) function in killing tumor targets. These data show that the inhibition of GSK-3 has differential effects on T-cell motility and CTL function where the negative effects on cell-cell interactions is overridden by the increased cytolytic potential of CTLs.

scholarly journals Glycogen synthase kinase 3 (GSK-3) controls T-cell motility andinteractions with antigen presenting cells

2020 ◽  
Author(s):  
Alison Taylor ◽  
Christopher E. Rudd
Keyword(s):  
T Cell ◽  
Cell Motility ◽  
Glycogen Synthase ◽  
Antigen Presenting Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Negative Effects ◽  
Serine Kinase ◽  
Multiple Substrates ◽  
Antigen Presenting

Abstract Objective:The threonine/serine kinase glycogen synthase kinase 3 (GSK-3) targets multiple substrates in T-cells and regulates the expression of Tbet and PD-1. However, it has been unclear whether GSK-3 has any effect on T-cell motility or their interactions with antigen presenting cells. Results: Here, we show that GSK-3 controls T-cell motilityand interactions with other cells. Inhibition of GSK-3, using structurally distinct inhibitors, reduced T-cell motility in terms of speed and distance travelled. Furthermore, SB415286 reduced the number of cell to cell contacts, however the duration of these established contacts with other cells did not differ in the presence of SB415286. This inhibition of motility did not affect the ability of GSK-3 inhibitors to enhance cytolytic T-cell (CTL) function in killing tumor targets. These data show that the inhibition of GSK-3 has differential effects on T-cell motility and CTL function where the negative effects on cell-cell interactions is overridden by the increased cytolytic potential of CTLs.

scholarly journals Spatial Regulation of MCAK Promotes Cell Polarization and Focal Adhesion Turnover to Drive Robust Cell Migration

2021 ◽  
pp. mbc.E20-05-0301
Author(s):  
Hailing Zong ◽  
Mark Hazelbaker ◽  
Christina Moe ◽  
Stephanie C. Ems-McClung ◽  
Ke Hu ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Cell Polarization ◽  
Asymmetric Distribution ◽  
Membrane Ruffling ◽  
Spatial Regulation ◽  
Directional Movement ◽  
Focal Adhesion Turnover

The asymmetric distribution of microtubule (MT) dynamics in migrating cells is important for cell polarization, yet the underlying regulatory mechanisms remain underexplored. Here, we addressed this question by studying the role of the MT depolymerase, MCAK, in the highly persistent migration of RPE-1 cells. MCAK knockdown leads to slowed migration and poor directional movement. Fixed and live cell imaging revealed that MCAK knockdown results in excessive membrane ruffling as well as defects in cell polarization and the maintenance of a major protrusive front. Additionally, loss of MCAK increases the lifetime of focal adhesions by decreasing their disassembly rate. These functions correlate with a spatial distribution of MCAK activity, wherein activity is higher in the trailing edge of cells compared to the leading edge. Overexpression of Rac1 has a dominant effect over MCAK activity, placing it downstream or in a parallel pathway to MCAK function in migration. Together, our data support a model in which the polarized distribution of MCAK activity and subsequent differential regulation of MT dynamics contribute to cell polarity, centrosome positioning and focal adhesion dynamics that all help facilitate robust directional migration. [Media: see text] [Media: see text]

scholarly journals Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1110 ◽  
Author(s):  
Przemysław Duda ◽  
Shaw M. Akula ◽  
Stephen L. Abrams ◽  
Linda S. Steelman ◽  
Alberto M. Martelli ◽  
...  
Keyword(s):  
Natural Products ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glycogen Synthase ◽  
Human Cancer ◽  
Glycogen Synthase Kinase 3 ◽  
Pharmaceutical Companies ◽  
Biochemical Processes ◽  
Multiple Substrates ◽  
Mtorc1 Pathway

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

Sign in / Sign up

Export Citation Format

Share Document