scholarly journals Protein kinase Cα (PKCα) regulates the nucleocytoplasmic shuttling of KRIT1

2020 ◽  
pp. jcs.250217
Author(s):  
Elisa De Luca ◽  
Andrea Perrelli ◽  
Harsha Swamy ◽  
Mariapaola Nitti ◽  
Mario Passalacqua ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Scaffolding Protein ◽  
Nuclear Accumulation ◽  
Nucleocytoplasmic Shuttling ◽  
Cell Matrix ◽  
Protein Kinase Cα ◽  
Subcellular Compartmentalization ◽  
Cell Matrix Adhesion

KRIT1 is a scaffolding protein that regulates multiple molecular mechanisms, including cell-cell and cell-matrix adhesion and redox homeostasis and signaling. However, rather little is known about how KRIT1 is itself regulated. KRIT1 is found in both the cytoplasm and the nucleus, yet the upstream signaling proteins and mechanisms that regulate KRIT1 nucleocytoplasmic shuttling are not well understood. Here, we identify a key role for protein kinase C (PKC). In particular, we found that PKC activation promotes the redox-dependent cytoplasmic localization of KRIT1, whereas inhibition of PKC or treatment with the antioxidant N-acetylcysteine leads to KRIT1 nuclear accumulation. Moreover, we demonstrated that the N-terminal region of KRIT1 is crucial for the ability of PKC to regulate KRIT1 nucleocytoplasmic shuttling, and may be a target for PKC-dependent regulatory phosphorylation events. Finally, we found that silencing of PKCα, but not PKCδ, inhibits phorbol-12-myristate-13-acetate (PMA)-induced cytoplasmic enrichment of KRIT1, suggesting a major role for PKCα in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKCα as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiopathological functions of this protein.

scholarly journals Arg interacts with cortactin to promote adhesion-dependent cell edge protrusion

2009 ◽  
Vol 185 (3) ◽  
pp. 503-519 ◽  
Author(s):  
Stefanie Lapetina ◽  
Christopher C. Mader ◽  
Kazuya Machida ◽  
Bruce J. Mayer ◽  
Anthony J. Koleske
Keyword(s):  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Sh2 Domain ◽  
Cell Edge ◽  
Cell Matrix ◽  
C Terminus ◽  
Dependent Cell ◽  
Src Homology ◽  
Fibroblast Adhesion ◽  
Cell Matrix Adhesion

The molecular mechanisms by which the Abelson (Abl) or Abl-related gene (Arg) kinases interface with the actin polymerization machinery to promote cell edge protrusions during cell–matrix adhesion are unclear. In this study, we show that interactions between Arg and the Arp2/3 complex regulator cortactin are essential to mediate actin-based cell edge protrusion during fibroblast adhesion to fibronectin. Arg-deficient and cortactin knockdown fibroblasts exhibit similar defects in adhesion-dependent cell edge protrusion, which can be restored via reexpression of Arg and cortactin. Arg interacts with cortactin via both binding and catalytic events. The cortactin Src homology (SH) 3 domain binds to a Pro-rich motif in the Arg C terminus. Arg mediates adhesion-dependent phosphorylation of cortactin, creating an additional binding site for the Arg SH2 domain. Mutation of residues that mediate Arg–cortactin interactions abrogate the abilities of both proteins to support protrusions, and the Nck adapter, which binds phosphocortactin, is also required. These results demonstrate that interactions between Arg, cortactin, and Nck1 are critical to promote adhesion-dependent cell edge protrusions.

scholarly journals Plexin-B2 orchestrates collective stem cell dynamics via actomyosin contractility, cytoskeletal tension and adhesion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chrystian Junqueira Alves ◽  
Rafael Dariolli ◽  
Jonathan Haydak ◽  
Sangjo Kang ◽  
Theodore Hannah ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Cell Physiology ◽  
Matrix Adhesion ◽  
Cell Matrix ◽  
Actomyosin Contractility ◽  
Cytoskeletal Tension ◽  
Cell Matrix Adhesion ◽  
Cell Cell

AbstractDuring morphogenesis, molecular mechanisms that orchestrate biomechanical dynamics across cells remain unclear. Here, we show a role of guidance receptor Plexin-B2 in organizing actomyosin network and adhesion complexes during multicellular development of human embryonic stem cells and neuroprogenitor cells. Plexin-B2 manipulations affect actomyosin contractility, leading to changes in cell stiffness and cytoskeletal tension, as well as cell-cell and cell-matrix adhesion. We have delineated the functional domains of Plexin-B2, RAP1/2 effectors, and the signaling association with ERK1/2, calcium activation, and YAP mechanosensor, thus providing a mechanistic link between Plexin-B2-mediated cytoskeletal tension and stem cell physiology. Plexin-B2-deficient stem cells exhibit premature lineage commitment, and a balanced level of Plexin-B2 activity is critical for maintaining cytoarchitectural integrity of the developing neuroepithelium, as modeled in cerebral organoids. Our studies thus establish a significant function of Plexin-B2 in orchestrating cytoskeletal tension and cell-cell/cell-matrix adhesion, therefore solidifying the importance of collective cell mechanics in governing stem cell physiology and tissue morphogenesis.

scholarly journals Review of PIP2 in Cellular Signaling, Functions and Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 8342
Author(s):  
Kalpana Mandal
Keyword(s):  
Molecular Mechanisms ◽  
Membrane Dynamics ◽  
Actin Dynamics ◽  
Cellular Functions ◽  
Phosphatidylinositol Bisphosphate ◽  
Cell Matrix ◽  
Intracellular Proteins ◽  
Specific Proteins ◽  
Cellular Compartments ◽  
Cell Matrix Adhesion

Phosphoinositides play a crucial role in regulating many cellular functions, such as actin dynamics, signaling, intracellular trafficking, membrane dynamics, and cell–matrix adhesion. Central to this process is phosphatidylinositol bisphosphate (PIP2). The levels of PIP2 in the membrane are rapidly altered by the activity of phosphoinositide-directed kinases and phosphatases, and it binds to dozens of different intracellular proteins. Despite the vast literature dedicated to understanding the regulation of PIP2 in cells over past 30 years, much remains to be learned about its cellular functions. In this review, we focus on past and recent exciting results on different molecular mechanisms that regulate cellular functions by binding of specific proteins to PIP2 or by stabilizing phosphoinositide pools in different cellular compartments. Moreover, this review summarizes recent findings that implicate dysregulation of PIP2 in many diseases

scholarly journals Protein Kinase Cα (Pkcα) Regulates the Nucleocytoplasmic Shuttling of KRIT1

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Angela Glading ◽  
Elisa De Luca ◽  
Andrea Perrelli ◽  
Harsha Swamy ◽  
Mariapaola Nitti ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nucleocytoplasmic Shuttling ◽  
Protein Kinase Cα

Protein kinase Cδ and apoptosis

2007 ◽  
Vol 35 (5) ◽  
pp. 1001-1004 ◽  
Author(s):  
M.E. Reyland
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Nuclear Accumulation ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Caspase Cleavage ◽  
Kinase C ◽  
Pkc Protein Kinase C ◽  
Apoptotic Activity

The PKC (protein kinase C) family regulates diverse cellular functions and specific isoforms have been shown to be critical regulators of cell proliferation and survival. In particular, PKCδ is known to be a critical pro-apoptotic signal in many cell types. Work in our laboratory has focused on understanding the molecular mechanisms through which PKCδ regulates apoptosis and on how the pro-apoptotic activity of this ubiquitous kinase is regulated such that cells only activate the apoptotic cascade when appropriate. We have identified multiple regulatory steps that activate the pro-apoptotic function of PKCδ in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKCδ in the regulatory domain, which facilitates translocation of the kinase from the cytoplasm to the nucleus. Active caspase 3 also accumulates in the nucleus under these conditions, resulting in caspase cleavage of PKCδ and generation of a constitutively activated form of PKCδ [δCF (PKCδ catalytic fragment)]. In contrast with PKCδ, δCF is constitutively present in the nucleus, and this nuclear accumulation of PKCδ is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKCδ is critical for cell survival and that caspase cleavage of PKCδ in the nucleus signals an irreversible commitment to apoptosis.

Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1

2021 ◽  
Vol 177 ◽  
pp. S61
Author(s):  
Andrea Perrelli ◽  
Elisa De Luca ◽  
Harsha Swamy ◽  
Mariapaola Nitti ◽  
Mario Passalacqua ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nucleocytoplasmic Shuttling ◽  
Protein Kinase Cα

scholarly journals Vascular cell-matrix adhesion in development and cancer

2021 ◽  
Author(s):  
Christina Arapatzi ◽  
Georgia Rouni ◽  
Vassiliki Kostourou
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Notch Signalling ◽  
Tumour Angiogenesis ◽  
Genetic Studies ◽  
Cell Matrix ◽  
Vascular Morphogenesis ◽  
Current State ◽  
Cell Matrix Adhesion

The development and homeostasis of vertebrate organisms depend on the “tree of life”, that is the intricate network of vascular tubes composed by endothelial cells attached to the basement membrane and surrounded by perivascular cells. Although many studies have revealed the fundamental role of cytokines, growth factors and Notch signalling in vascular morphogenesis, we still lack sufficient understanding of the molecular mechanisms controlling the various steps of the angiogenic processes. Emerging data highlight that cell adhesions are key players in vascular morphogenesis. In this review, we focus on endothelial cells and we present the current state of knowledge regarding the role of cell-matrix adhesions in developmental and tumour angiogenesis, attained mainly from genetic studies and animal models.

scholarly journals Actin Dynamics Associated with Focal Adhesions

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Corina Ciobanasu ◽  
Bruno Faivre ◽  
Christophe Le Clainche
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Body Force ◽  
Focal Adhesions ◽  
Stress Fibers ◽  
Actin Dynamics ◽  
Actin Assembly ◽  
Force Transmission ◽  
Cell Matrix ◽  
Cell Matrix Adhesion

Cell-matrix adhesion plays a major role during cell migration. Proteins from adhesion structures connect the extracellular matrix to the actin cytoskeleton, allowing the growing actin network to push the plasma membrane and the contractile cables (stress fibers) to pull the cell body. Force transmission to the extracellular matrix depends on several parameters including the regulation of actin dynamics in adhesion structures, the contractility of stress fibers, and the mechanosensitive response of adhesion structures. Here we highlight recent findings on the molecular mechanisms by which actin assembly is regulated in adhesion structures and the molecular basis of the mechanosensitivity of focal adhesions.

scholarly journals Nucleocytoplasmic Shuttling of STATs. A Target for Intervention?

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1815
Author(s):  
Sabrina Ernst ◽  
Gerhard Müller-Newen
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Nuclear Accumulation ◽  
Special Focus ◽  
Tyrosine Residue ◽  
Signal Transducer ◽  
Specific Intervention ◽  
Nucleocytoplasmic Shuttling ◽  
Stat Proteins

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear accumulation is shared by all STAT family members but mechanisms of nuclear translocation vary between different STATs. These differences offer opportunities for specific intervention. To achieve this, the molecular mechanisms of nucleocytoplasmic shuttling of STATs need to be understood in more detail. In this review we will give an overview on the various aspects of nucleocytoplasmic shuttling of latent and activated STATs with a special focus on STAT3 and STAT5. Potential targets for cancer treatment will be identified and discussed.

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