P21-Activated Kinase 1 Overactivates in Eutopic Endometrium of Adenomyosis

2018 ◽  
Vol 26 (9) ◽  
pp. 1235-1242 ◽  
Author(s):  
Weiwen Zuo ◽  
Xiaoyi Wu ◽  
Haiou Liu ◽  
Congjian Xu
Keyword(s):  
Rho Gtpases ◽  
Active Form ◽  
Glandular Cell ◽  
Apical Surface ◽  
Eutopic Endometrium ◽  
Cytoskeletal Remodeling ◽  
Small Rho Gtpases ◽  
Gynecological Disease ◽  
P21 Activated Kinase ◽  
Pak1 Expression

Adenomyosis is a common gynecological disease, characterized by the existence of endometrium in the myometrium. The pathogenesis of adenomyosis is not fully understood. P21-activated kinase 1 (PAK1) is an effector of small Rho GTPases including CDC42 and RAC1 and plays various roles in cellular biology, especially cytoskeletal remodeling. This study aimed to evaluate whether the expression and activation of PAK1 in adenomyosis were different from normal. Immunohistochemistry was performed to evaluate the expression of PAK1 and its active form phosphorylated-PAK1 (pPAK1) semi-quantitatively in women with and without adenomyosis. Immunofluorescence was performed to locate the distribution of pPAK1. This study found that PAK1 in eutopic endometrium of adenomyosis was overactivated compared to normal. Phosphorylated-PAK1 assembled along the apical surface of glandular cell membrane. In ectopic lesions, PAK1 expression decreased and its activation returned to the baseline. The expression of pPAK1 correlated with the frequency of reproduction. These findings suggest that PAK1 overactivation in the endometrium may be an important event during the development of adenomyosis, meanwhile, decreased phosphorylation may assist to form lesions.

scholarly journals Constitutive p21-activated Kinase (PAK) Activation in Breast Cancer Cells as a Result of Mislocalization of PAK to Focal Adhesions

2004 ◽  
Vol 15 (6) ◽  
pp. 2965-2977 ◽  
Author(s):  
Mary R. Stofega ◽  
Luraynne C. Sanders ◽  
Elisabeth M. Gardiner ◽  
Gary M. Bokoch
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Rho Gtpases ◽  
Breast Cancer Cells ◽  
Kinase Activity ◽  
Focal Adhesions ◽  
Breast Cancer Cell Lines ◽  
Cytoskeletal Remodeling ◽  
P21 Activated Kinase ◽  
Pak Kinase

Cytoskeletal remodeling is critical for cell adhesion, spreading, and motility. p21-activated kinase (PAK), an effector molecule of the Rho GTPases Rac and Cdc42, has been implicated in cytoskeletal remodeling and cell motility. PAK kinase activity and subcellular distribution are tightly regulated by rapid and transient localized Rac and Cdc42 activation, and by interactions mediated by adapter proteins. Here, we show that endogenous PAK is constitutively activated in certain breast cancer cell lines and that this active PAK is mislocalized to atypical focal adhesions in the absence of high levels of activated Rho GTPases. PAK localization to focal adhesions in these cells is independent of PAK kinase activity, NCK binding, or GTPase binding, but requires the association of PAK with PIX. Disruption of the PAK–PIX interaction with competitive peptides displaces PAK from focal adhesions and results in a substantial reduction in PAK hyperactivity. Moreover, disruption of the PAK–PIX interaction is associated with a dramatic decrease of PIX and paxillin in focal adhesions, indicating that PAK localization to these structures via PIX is required for the maintenance of paxillin- and PIX-containing focal adhesions. Abnormal regulation of PAK localization and activity may contribute to the tumorigenic properties of certain breast cancer cells.

scholarly journals PAK and other Rho-associated kinases – effectors with surprisingly diverse mechanisms of regulation

2005 ◽  
Vol 386 (2) ◽  
pp. 201-214 ◽  
Author(s):  
Zhou-shen ZHAO ◽  
Ed MANSER
Keyword(s):  
Rho Gtpases ◽  
Cell Biology ◽  
Rho Gtpase ◽  
Rho Kinase ◽  
Molecular Switches ◽  
Eukaryotic Cell ◽  
Effector Proteins ◽  
Downstream Effector ◽  
P21 Activated Kinase ◽  
Do So

The Rho GTPases are a family of molecular switches that are critical regulators of signal transduction pathways in eukaryotic cells. They are known principally for their role in regulating the cytoskeleton, and do so by recruiting a variety of downstream effector proteins. Kinases form an important class of Rho effector, and part of the biological complexity brought about by switching on a single GTPase results from downstream phosphorylation cascades. Here we focus on our current understanding of the way in which different Rho-associated serine/threonine kinases, denoted PAK (p21-activated kinase), MLK (mixed-lineage kinase), ROK (Rho-kinase), MRCK (myotonin-related Cdc42-binding kinase), CRIK (citron kinase) and PKN (protein kinase novel), interact with and are regulated by their partner GTPases. All of these kinases have in common an ability to dimerize, and in most cases interact with a variety of other proteins that are important for their function. A diversity of known structures underpin the Rho GTPase–kinase interaction, but only in the case of PAK do we have a good molecular understanding of kinase regulation. The ability of Rho GTPases to co-ordinate spatial and temporal phosphorylation events explains in part their prominent role in eukaryotic cell biology.

scholarly journals Cortical Interneuron Development: a role for small Rho GTPases

2021 ◽  
Author(s):  
Zouzana Kounoupa ◽  
Domna Karagogeos
Keyword(s):  
Cell Cycle ◽  
Rho Gtpases ◽  
Double Mutant ◽  
Epileptic Seizures ◽  
Transgenic Animals ◽  
Postnatal Period ◽  
Cell Therapies ◽  
Cortical Interneurons ◽  
Small Rho Gtpases ◽  
And Migration

GABAergic interneurons control cortical excitation/inhibition balance and are implicated in severe neurodevelopmental disorders. In contrast to the multiplicity of signals underlying the generation and migration of cortical interneurons, the intracellular proteins mediating the response to these cues are mostly unknown. We have demonstrated the unique and diverse roles of the Rho GTPases Rac1 and 3 in cell cycle and morphology in transgenic animals where Rac1 and Rac1/3 were ablated specifically in cortical interneurons. In the Rac1 mutant, progenitors delay their cell cycle exit probably due to a prolonged G1 phase resulting in a cortex with 50% reductions in interneurons and an imbalance of excitation/inhibition in cortical circuits. This disruption in GABAergic inhibition alters glutamatergic function in the adult cortex that could be reversed by enhancement of GABAergic function during an early postnatal period. Furthermore, this disruption disturbs the neuronal synchronization in the adult cortex. In the double mutant, additional severe cytoskeletal defects result in an 80% interneuron decrease. Both lines die from epileptic seizures postnatally. We have made progress towards characterizing the cell cycle defect in Rac1 mutant interneuron progenitors, determining the morphological and synaptic characteristics of single and double mutant interneurons and identifying some of the molecular players by which Racs exert their actions by proteomic analysis. In our present work, we review these studies and discuss open questions and future perspectives. We expect that our data will contribute to the understanding of the function of cortical interneurons, especially since preclinical models of interneuron-based cell therapies are being established.

scholarly journals Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Wanli Ma ◽  
Xiaohe Wang ◽  
Chunhui Wang ◽  
Mingzhi Gong ◽  
Peng Ren
Keyword(s):  
Articular Cartilage ◽  
Cartilage Destruction ◽  
Related Factors ◽  
Osteoarthritic Cartilage ◽  
Resident Cell ◽  
Joint Disorder ◽  
Osteoarthritis Chondrocytes ◽  
P21 Activated Kinase ◽  
Pak1 Expression

Abstract Osteoarthritis is mainly caused by a degenerative joint disorder, which is characterized by the gradual degradation of articular cartilage and synovial inflammation. The chondrocyte, the unique resident cell type of articular cartilage, is crucial for the development of osteoarthritis. Previous studies revealed that P21-activated kinase-1 (PAK1) was responsible for the initiation of inflammation. The purpose of the present study was to determine the potential role of PAK1 in osteoarthritis. The level of PAK1 expression was measured by Western blot and quantitative real-time PCR in articular cartilage from osteoarthritis model rats and patients with osteoarthritis. In addition, the functional role of aberrant PAK1 expression was detected in the chondrocytes. We found that the expression of PAK1 was significantly increased in chondrocytes treated with osteoarthritis-related factors. Increased expression of PAK1 was also observed in knee articular cartilage samples from patients with osteoarthritis and osteoarthritis model rats. PAK1 was found to inhibit chondrocytes proliferation and to promote the production of inflammatory cytokines in cartilages chondrocytes. Furthermore, we found that PAK1 modulated the production of extracellular matrix and cartilage degrading enzymes in chondrocytes. Results of the present studies demonstrated that PAK1 might play an important role in the pathogenesis of osteoarthritis.

Small Rho GTPases in the control of cell shape and mobility

2013 ◽  
Vol 71 (9) ◽  
pp. 1703-1721 ◽  
Author(s):  
Arun Murali ◽  
Krishnaraj Rajalingam
Keyword(s):  
Rho Gtpases ◽  
Cell Shape ◽  
Small Rho Gtpases

Regulation of cytoskeletal mechanics and cell growth by myosin light chain phosphorylation

1998 ◽  
Vol 275 (5) ◽  
pp. C1349-C1356 ◽  
Author(s):  
Shuang Cai ◽  
Lidija Pestic-Dragovich ◽  
Martha E. O’Donnell ◽  
Ning Wang ◽  
Donald Ingber ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
Light Chain ◽  
Intracellular Signaling ◽  
Myosin Light Chain ◽  
Active Form ◽  
Fold Increase ◽  
Mitogen Activated Protein Kinase ◽  
Apical Surface ◽  
Myosin Light Chain Phosphorylation

The role of myosin light chain phosphorylation in regulating the mechanical properties of the cytoskeleton was studied in NIH/3T3 fibroblasts expressing a truncated, constitutively active form of smooth muscle myosin light chain kinase (tMK). Cytoskeletal stiffness determined by quantifying the force required to indent the apical surface of adherent cells showed that stiffness was increased twofold in tMK cells compared with control cells expressing the empty plasmid (Neo cells). Cytoskeletal stiffness quantified using magnetic twisting cytometry showed an ∼1.5-fold increase in stiffness in tMK cells compared with Neo cells. Electronic volume measurements on cells in suspension revealed that tMK cells had a smaller volume and are more resistant to osmotic swelling than Neo cells. tMK cells also have smaller nuclei, and activation of mitogen-activated protein kinase (MAP kinase) and translocation of MAP kinase to the nucleus are slower in tMK cells than in control cells. In tMK cells, there is also less bromodeoxyuridine incorporation, and the doubling time is increased. These data demonstrate that increased myosin light chain phosphorylation correlates with increased cytoskeletal stiffness and suggest that changing the mechanical characteristics of the cytoskeleton alters the intracellular signaling pathways that regulate cell growth and division.

scholarly journals CB-15 * NKCC1 REGULATES MIGRATION CAPACITY OF GLIOBLASTOMA TUMOR INITIATING CELLS BY MODULATING ACTIN CYTOSKELETON THROUGH SMALL RHO GTPASES

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v43-v44 ◽  
Author(s):  
P. Schiapparelli ◽  
R. Magana-Maldonado ◽  
S. Hamilla ◽  
L. Sibener ◽  
J. C. Martinez-Gutierrez ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Tumor Initiating Cells ◽  
Small Rho Gtpases ◽  
Migration Capacity
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