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 DAPP1: a dual adaptor for phosphotyrosine and 3-phosphoinositides

1999 ◽  
Vol 342 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Simon DOWLER ◽  
Richard A. CURRIE ◽  
C. Peter DOWNES ◽  
Dario R. ALESSI
Keyword(s):  
Amino Acid ◽  
Sh2 Domain ◽  
Ph Domain ◽  
Phosphorylated Proteins ◽  
High Affinity ◽  
C Terminus ◽  
Acid Protein ◽  
N Terminus ◽  
Src Homology ◽  
Amino Acid Protein

We have identified a novel 280 amino acid protein which contains a putative myristoylation site at its N-terminus followed by an Src homology (SH2) domain and a pleckstrin homology (PH) domain at its C-terminus. It has been termed dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1). DAPP1 is widely expressed and exhibits high-affinity interactions with PtdIns(3,4,5)P3 and PtdIns(3,4)P2, but not with other phospholipids tested. These observations predict that DAPP1 will interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and may therefore play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P3 and PtdIns(3,4)P2.

scholarly journals Zasp is required for the assembly of functional integrin adhesion sites

2007 ◽  
Vol 179 (7) ◽  
pp. 1583-1597 ◽  
Author(s):  
Klodiana Jani ◽  
Frieder Schöck
Keyword(s):  
Focal Adhesions ◽  
Myotendinous Junction ◽  
Lim Domain ◽  
Transmembrane Receptors ◽  
Cell Matrix ◽  
Adhesion Sites ◽  
Alternatively Spliced ◽  
Dependent Cell ◽  
Cell Matrix Adhesion ◽  
Myotendinous Junctions

The integrin family of heterodimeric transmembrane receptors mediates cell–matrix adhesion. Integrins often localize in highly organized structures, such as focal adhesions in tissue culture and myotendinous junctions in muscles. Our RNA interference screen for genes that prevent integrin-dependent cell spreading identifies Z band alternatively spliced PDZ-motif protein (zasp), encoding the only known Drosophila melanogaster Alp/Enigma PDZ-LIM domain protein. Zasp localizes to integrin adhesion sites and its depletion disrupts integrin adhesion sites. In tissues, Zasp colocalizes with βPS integrin in myotendinous junctions and with α-actinin in muscle Z lines. Zasp also physically interacts with α-actinin. Fly larvae lacking Zasp do not form Z lines and fail to recruit α-actinin to the Z line. At the myotendinous junction, muscles detach in zasp mutants with the onset of contractility. Finally, Zasp interacts genetically with integrins, showing that it regulates integrin function. Our observations point to an important function for Zasp in the assembly of integrin adhesion sites both in cell culture and in tissues.

scholarly journals Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor FcγRIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap

2004 ◽  
Vol 279 (50) ◽  
pp. 51931-51938 ◽  
Author(s):  
Isabelle Isnardi ◽  
Renaud Lesourne ◽  
Pierre Bruhns ◽  
Wolf H. Fridman ◽  
John C. Cambier ◽  
...  
Keyword(s):  
Cell Activation ◽  
Sh2 Domain ◽  
Scaffold Proteins ◽  
Src Homology 2 ◽  
Dependent Cell ◽  
Trimolecular Complex ◽  
Src Homology ◽  
Inositol Phosphatases ◽  
Necessary And Sufficient ◽  
Activation Motif

FcγRIIB are low-affinity receptors for IgG that contain an immunoreceptor tyrosine-based inhibition motif (ITIM) and inhibit immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. When coaggregated with ITAM-bearing receptors, FcγRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5′-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcγRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2. We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcγRIIB is required for SHIP1/2 to be coprecipitated with the receptor. This motif functions as a docking site for the SH2 domain-containing adapters Grb2 and Grap. These adapters interact via their C-terminal SH3 domain with SHIP1/2 to form a stable receptor-phosphatase-adapter trimolecular complex. Both Grb2 and Grap are required for an optimal coprecipitation of SHIP with FcγRIIB, but one adapter is sufficient for the phosphatase to coprecipitate in a detectable manner with the receptors. In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcγRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

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 Mechanosensing during directed cell migration requires dynamic actin polymerization at focal adhesions

2019 ◽  
Vol 218 (12) ◽  
pp. 4215-4235 ◽  
Author(s):  
Julieann I. Puleo ◽  
Sara S. Parker ◽  
Mackenzie R. Roman ◽  
Adam W. Watson ◽  
Kiarash Rahmani Eliato ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Focal Adhesions ◽  
Mechanical Stimuli ◽  
Matrix Stiffness ◽  
Cellular Behavior ◽  
Cytoskeletal Remodeling ◽  
Cell Matrix ◽  
Directed Cell Migration ◽  
Cell Matrix Adhesion

The mechanical properties of a cell’s microenvironment influence many aspects of cellular behavior, including cell migration. Durotaxis, the migration toward increasing matrix stiffness, has been implicated in processes ranging from development to cancer. During durotaxis, mechanical stimulation by matrix rigidity leads to directed migration. Studies suggest that cells sense mechanical stimuli, or mechanosense, through the acto-myosin cytoskeleton at focal adhesions (FAs); however, FA actin cytoskeletal remodeling and its role in mechanosensing are not fully understood. Here, we show that the Ena/VASP family member, Ena/VASP-like (EVL), polymerizes actin at FAs, which promotes cell-matrix adhesion and mechanosensing. Importantly, we show that EVL regulates mechanically directed motility, and that suppression of EVL expression impedes 3D durotactic invasion. We propose a model in which EVL-mediated actin polymerization at FAs promotes mechanosensing and durotaxis by maturing, and thus reinforcing, FAs. These findings establish dynamic FA actin polymerization as a central aspect of mechanosensing and identify EVL as a crucial regulator of this process.

scholarly journals Arginylation-dependent regulation of a proteolytic product of talin is essential for cell–cell adhesion

2012 ◽  
Vol 197 (6) ◽  
pp. 819-836 ◽  
Author(s):  
Fangliang Zhang ◽  
Sougata Saha ◽  
Anna Kashina
Keyword(s):  
Cell Adhesion ◽  
Cell Attachment ◽  
Adhesion Formation ◽  
Cell Matrix ◽  
Intracellular Regulation ◽  
Dependent Cell ◽  
Cell Matrix Adhesion ◽  
Proteolytic Product ◽  
Cell Cell

Talin is a large scaffolding molecule that plays a major role in integrin-dependent cell–matrix adhesion. A role for talin in cell–cell attachment through cadherin has never been demonstrated, however. Here, we identify a novel calpain-dependent proteolytic cleavage of talin that results in the release of a 70-kD C-terminal fragment, which serves as a substrate of posttranslational arginylation. The intracellular levels of this fragment closely correlated with the formation of cell–cell adhesions, and this fragment localized to cadherin-containing cell–cell contacts. Moreover, reintroduction of this fragment rescued the cell–cell adhesion defects in arginyltransferase (Ate1) knockout cells, which normally have a very low level of this fragment. Arginylation of this fragment further enhanced its ability to rescue cell–cell adhesion formation. In addition, arginylation facilitated its turnover, suggesting a dual role of arginylation in its intracellular regulation. Thus, our work identifies a novel proteolytic product of talin that is regulated by arginylation and a new role of talin in cadherin-dependent cell–cell adhesion.

scholarly journals Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma

2014 ◽  
Vol 7 ◽  
pp. BCI.S18863 ◽  
Author(s):  
Lisette P. Yco ◽  
Gabor Mocz ◽  
John Opoku-Ansah ◽  
André S. Bachmann
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Computational Models ◽  
Sh2 Domain ◽  
Withaferin A ◽  
Tumor Cell Death ◽  
Src Homology 2 ◽  
Stat3 Phosphorylation ◽  
Dependent Cell ◽  
Src Homology

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phosphotyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM.

scholarly journals Phosphorylated YDXV Motifs and Nck SH2/SH3 Adaptors Act Cooperatively To Induce Actin Reorganization

2008 ◽  
Vol 28 (6) ◽  
pp. 2035-2046 ◽  
Author(s):  
Ivan M. Blasutig ◽  
Laura A. New ◽  
Ajitha Thanabalasuriar ◽  
Thamara K. Dayarathna ◽  
Marilyn Goudreault ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Molecular Mimicry ◽  
Adaptor Proteins ◽  
Sh2 Domain ◽  
Local Concentration ◽  
Binding Motifs ◽  
Actin Reorganization ◽  
Adhesion Protein ◽  
Src Homology

ABSTRACT We have analyzed the means by which the Nck family of adaptor proteins couples adhesion proteins to actin reorganization. The nephrin adhesion protein is essential for the formation of actin-based foot processes in glomerular podocytes. The clustering of nephrin induces its tyrosine phosphorylation, Nck recruitment, and sustained localized actin polymerization. Any one of three phosphorylated (p)YDXV motifs on nephrin is sufficient to recruit Nck through its Src homology 2 (SH2) domain and induce localized actin polymerization at these clusters. Similarly, Nck SH3 mutants in which only the second or third SH3 domain is functional can mediate nephrin-induced actin polymerization. However, combining such nephrin and Nck mutants attenuates actin polymerization at nephrin-Nck clusters. We propose that the multiple Nck SH2-binding motifs on nephrin and the multiple SH3 domains of Nck act cooperatively to recruit the high local concentration of effectors at sites of nephrin activation that is required to initiate and maintain actin polymerization in vivo. We also find that YDXV motifs in the Tir protein of enteropathogenic Escherichia coli and nephrin are functionally interchangeable, indicating that Tir reorganizes the actin cytoskeleton by molecular mimicry of nephrin-like signaling. Together, these data identify pYDXV/Nck signaling as a potent and portable mechanism for physiological and pathological actin regulation.

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