scholarly journals Laminin Polymerization Induces a Receptor–Cytoskeleton Network

1999 ◽  
Vol 145 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Holly Colognato ◽  
Donald A. Winkelmann ◽  
Peter D. Yurchenco
Keyword(s):  
Self Assembly ◽  
Receptor Occupancy ◽  
Basement Membranes ◽  
Laminin Receptor ◽  
Cell Surfaces ◽  
Actin Reorganization ◽  
Receptor Interactions ◽  
Cooperative Process ◽  
A Cell ◽  
Receptor Ligation

The transition of laminin from a monomeric to a polymerized state is thought to be a crucial step in the development of basement membranes and in the case of skeletal muscle, mutations in laminin can result in severe muscular dystrophies with basement membrane defects. We have evaluated laminin polymer and receptor interactions to determine the requirements for laminin assembly on a cell surface and investigated what cellular responses might be mediated by this transition. We found that on muscle cell surfaces, laminins preferentially polymerize while bound to receptors that included dystroglycan and α7β1 integrin. These receptor interactions are mediated through laminin COOH-terminal domains that are spatially and functionally distinct from NH2-terminal polymer binding sites. This receptor-facilitated self-assembly drives rearrangement of laminin into a cell-associated polygonal network, a process that also requires actin reorganization and tyrosine phosphorylation. As a result, dystroglycan and integrin redistribute into a reciprocal network as do cortical cytoskeleton components vinculin and dystrophin. Cytoskeletal and receptor reorganization is dependent on laminin polymerization and fails in response to receptor occupancy alone (nonpolymerizing laminin). Preferential polymerization of laminin on cell surfaces, and the resulting induction of cortical architecture, is a cooperative process requiring laminin– receptor ligation, receptor-facilitated self-assembly, actin reorganization, and signaling events.

Recent Advances in the Function of the 67 kDa Laminin Receptor and its Targeting for Personalized Therapy in Cancer

2017 ◽  
Vol 23 (32) ◽  
pp. 4745-4757 ◽  
Author(s):  
Ada Pesapane ◽  
Pia Ragno ◽  
Carmine Selleri ◽  
Nunzia Montuori
Keyword(s):  
Cell Adhesion ◽  
Cancer Progression ◽  
Ribosome Biogenesis ◽  
Critical Role ◽  
Protein Translation ◽  
Basement Membranes ◽  
Laminin Receptor ◽  
Cell Surface Receptor ◽  
Future Application ◽  
Neoplastic Cells

The 67 kDa high affinity laminin receptor (67LR) is a non-integrin cell surface receptor for laminin, the major component of basement membranes. Interactions between 67LR and laminin play a major role in mediating cell adhesion, migration, proliferation and survival. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), most probably by fatty acid acylation. Interestingly, 37LRP, also called p40 or OFA/iLR (oncofetal antigen/immature laminin receptor), is a multifunctional protein with a dual activity in the cytoplasm and in the nucleus. In the cytoplasm, 37LRP it is associated with the 40S subunit of ribosome, playing a critical role in protein translation and ribosome biogenesis while in the nucleus it is tightly associated with nuclear structures, and bound to components of the cytoskeleton, such as tubulin and actin. 67LR is mainly localized in the cell membrane, concentrated in lipid rafts. Acting as a receptor for laminin is not the only function of 67LR; indeed, it also acts as a receptor for viruses, bacteria and prions. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. The primary function of 67LR in cancer is to promote tumor cell adhesion to basement membranes, the first step in the invasion-metastasis cascade. Thus, 67LR is overexpressed in neoplastic cells as compared to their normal counterparts and its overexpression is considered a molecular marker of metastatic aggressiveness in cancer of many tissues, including breast, lung, ovary, prostate, stomach, thyroid and also in leukemia and lymphoma. Thus, inhibiting 67LR binding to laminin could be a feasible approach to block cancer progression. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer invasion and metastasis and reviewing the various therapeutic options targeting this receptor that could have a promising future application.

scholarly journals Epistatic dissection of laminin-receptor interactions in dystrophic zebrafish muscle

2012 ◽  
Vol 21 (21) ◽  
pp. 4718-4731 ◽  
Author(s):  
T. E. Sztal ◽  
C. Sonntag ◽  
T. E. Hall ◽  
P. D. Currie
Keyword(s):  
Laminin Receptor ◽  
Receptor Interactions

SEM localization of cell-surface-associated fibronectin in the cranium of chick embryos utilizing immunolatex microspheres

Development ◽  
1984 ◽  
Vol 80 (1) ◽  
pp. 175-195
Author(s):  
Stephen Meier ◽  
Christopher Drake
Keyword(s):  
Basement Membranes ◽  
Chick Embryos ◽  
Preimmune Serum ◽  
Fluorescent Staining ◽  
Cell Surfaces ◽  
Cell Soma ◽  
Rabbit Igg ◽  
Neural Ectoderm ◽  
Cranial Neural Crest Cells ◽  
Testicular Hyaluronidase

Fibronectin has been localized to basement membranes and cell surfaces with the light microscope by fluorescent staining of thick sections, and with the TEM by immunoperoxidase reaction. However, these methods are limited because it is difficult to appreciate the patterned distribution of fibronectin from sectioned material. We have developed a probe for fibronectin that facilitates its identification with the SEM. Our probe consists of two parts; the first component is a derivatized methacrylate microsphere 90 nm in diameter, linked to purified sheep anti-rabbit IgG. The second component is anti-fibronectin IgG raised in rabbits. Stage-3 to -12 chick embryos were fixed and the ectoderm covering the cranial mesoderm was removed. Embryos were treated with testicular hyaluronidase, exposed to rabbit antifibronectin IgG and finally to sheep anti-rabbit IgG conjugated microspheres. As expected, the basal lamina of surface and neural ectoderm as well as the remaining fibrous ECM were heavily decorated with microspheres, whereas control embryos treated with preimmune serum were beadless. Fibronectin was localized on the cell soma and processes of primary mesenchyme as early as stage 3. In addition, it was possible to decorate to various extents, populations of prosencephalic, mesencephalic, and rhombencephalic cranial neural crest cells. Our studies suggest that fibronectin is present in the cranium of chick embryos at earlier times than heretofore realized, and that fibronectin accumulates in a cranial to caudal gradient that reflects the sequential differentiation of the embryonic axis.

Mechanical competition alters the cellular interpretation of an endogenous genetic program

2021 ◽  
Vol 220 (11) ◽  
Author(s):  
Sourabh Bhide ◽  
Denisa Gombalova ◽  
Gregor Mönke ◽  
Johannes Stegmaier ◽  
Valentyna Zinchenko ◽  
...  
Keyword(s):  
Genetic Program ◽  
Cell Behavior ◽  
Mechanical Stimuli ◽  
Apical Constriction ◽  
Actin Reorganization ◽  
Ductile Materials ◽  
Nonlinear Mechanical ◽  
A Cell ◽  
Contractile Forces ◽  
Strain Responses

The intrinsic genetic program of a cell is not sufficient to explain all of the cell’s activities. External mechanical stimuli are increasingly recognized as determinants of cell behavior. In the epithelial folding event that constitutes the beginning of gastrulation in Drosophila, the genetic program of the future mesoderm leads to the establishment of a contractile actomyosin network that triggers apical constriction of cells and thereby tissue folding. However, some cells do not constrict but instead stretch, even though they share the same genetic program as their constricting neighbors. We show here that tissue-wide interactions force these cells to expand even when an otherwise sufficient amount of apical, active actomyosin is present. Models based on contractile forces and linear stress–strain responses do not reproduce experimental observations, but simulations in which cells behave as ductile materials with nonlinear mechanical properties do. Our models show that this behavior is a general emergent property of actomyosin networks in a supracellular context, in accordance with our experimental observations of actin reorganization within stretching cells.

Structural models for the self-assembly and microtubule interactions of gamma-, delta- and epsilon-tubulin

2001 ◽  
Vol 114 (2) ◽  
pp. 413-422 ◽  
Author(s):  
Y.F. Inclan ◽  
E. Nogales
Keyword(s):  
Self Assembly ◽  
Structural Models ◽  
Dependent Manner ◽  
Gamma Delta ◽  
Sequence Comparisons ◽  
Alpha Tubulin ◽  
A Cell ◽  
Gamma Tubulin ◽  
Cycle Dependent ◽  
Key Residues

alphabeta-tubulin heterodimers self-assemble to form microtubules nucleated by gamma-tubulin in the cell. Gamma-tubulin is believed to recruit the alphabeta-tubulin dimers that form the minus ends of microtubules, but the molecular mechanism of this action remains a matter of heated controversy. Still less is known about the function and molecular interactions of delta-tubulin and epsilon-tubulin. delta-tubulin may seed the formation of the C triplet tubules in the basal bodies of Chlamydomonas and epsilon-tubulin is known to localize to the centrosome in a cell cycle-dependent manner. Using the structure of alphabeta tubulin as a model, we have analyzed the sequences of gamma-, delta- and epsilon-tubulin in regions corresponding to different polymerization interfaces in the tubulin alphabeta dimer. The sequence comparisons sometimes show clear conservation, pointing to similar types of contacts being functionally important for the new tubulin considered. Conversely, certain surfaces show marked differences that rule out equivalent interactions for non-microtubular tubulins. This sequence/structure analysis has led us to structural models of how these special tubulins may be involved in protein-protein contacts that affect microtubule self-assembly. delta-tubulin most likely interacts longitudinally with alpha-tubulin at the minus ends of microtubules, while epsilon-tubulin most likely binds to the plus end of beta-tubulin. Conservation of key residues in gamma-tubulin suggests that it is capable of longitudinal self-assembly. The implications for the protofilament and template models of nucleation are considered.

scholarly journals Inhibition of laminin self-assembly and interaction with type IV collagen by antibodies to the terminal domain of the long arm.

1986 ◽  
Vol 103 (5) ◽  
pp. 1689-1697 ◽  
Author(s):  
A S Charonis ◽  
E C Tsilibary ◽  
T Saku ◽  
H Furthmayr
Keyword(s):  
Self Assembly ◽  
Binding Sites ◽  
Type Iv Collagen ◽  
Specific Interaction ◽  
Basement Membranes ◽  
Complex Domain ◽  
Peptide Fragment ◽  
Type Iv ◽  
Collagen Molecules

Laminin is a major glycoprotein of the basement membrane. Although its precise localization and orientation within this structure is unknown, it is presumably anchored to other macromolecules such as type IV collagen or proteoheparan sulfate. In vitro, laminin has the ability to self-assemble and to bind to type IV collagen molecules at distinct sites. To identify more precisely the domains of the complex, cross-shaped laminin molecule that are involved in these interactions, images of laminin-laminin dimers and laminin-type IV collagen complexes obtained by the rotary shadowing method were analyzed. We observed that the complex domain at the end of the long arm of laminin is predominantly involved in these interactions. By using Fab fragments of antibodies specific for a peptide fragment derived from this complex domain, it is shown that laminin self-assembly is inhibited in their presence, as measured by turbidity and by electron microscopy. In addition, these antibodies inhibit the specific interaction of laminin with type IV collagen. These data suggest that the complex domain at the end of the long arm of laminin contains binding sites of potential importance for the assembly of basement membranes.

scholarly journals Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation

2014 ◽  
Author(s):  
Ivana Petrovska ◽  
Elisabeth Nüske ◽  
Matthias C Munder ◽  
Gayathrie Kulasegaran ◽  
Liliana Malinovska ◽  
...  
Keyword(s):  
Metabolic Enzymes ◽  
Low Ph ◽  
General Mechanism ◽  
Filament Formation ◽  
Ph Change ◽  
Cooperative Process ◽  
A Cell ◽  
Enzymatic Inactivation ◽  
Physical Organization

One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involves back-to-back stacking of cylindrical homo-decamers into filaments that associate laterally to form higher order fibrils. Other metabolic enzymes also assemble into filaments at low pH. Hence, we propose that filament formation is a general mechanism to inactivate and store key metabolic enzymes during a state of advanced cellular starvation. These findings have broad implications for understanding the interplay between nutritional stress, the metabolism and the physical organization of a cell.

scholarly journals High Molecular Weight Kininogen Peptides Inhibit the Formation of Kallikrein on Endothelial Cell Surfaces and Subsequent Urokinase-Dependent Plasmin Formation

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 690-697 ◽  
Author(s):  
Yingzhang Lin ◽  
Robert B. Harris ◽  
Wuyi Yan ◽  
Keith R. McCrae ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Structural Information ◽  
Umbilical Vein ◽  
High Molecular Weight Kininogen ◽  
Cell Surfaces ◽  
Free System ◽  
Order Of Magnitude ◽  
A Cell ◽  
Umbilical Vein Endothelial Cells

A sequence of 31 amino acids (S565-K595) in domain 6 of the light chain of high molecular weight kininogen (HK) has previously been shown to be responsible for the binding of plasma prekallikrein (PK) or kallikrein. To find effective peptides that might block binding between HK and PK on cell surfaces, a new series of synthetic peptides has now been prepared that incorporates portions of this binding domain sequence. For mapping the minimal sequence within HK, these new peptides were tested for their ability to compete with HK for binding PK in a cell-free system and on human umbilical vein endothelial cells (HUVEC). In the former, at pH 7.4, the kds for binding between kallikrein and either D567-K595, S565-P594, D567-S593, or D567-T591 were all similar to that for the binding of S565-K595 (0.2 to 0.4 μmol/L), but those for the binding of D568-K595, W569-K595, and D567-P589 were an order of magnitude greater (kd = 2 to 5 μmol/L). D567-S586, the shortest chain length of the N- and C-terminal truncation sequences tested, does not effectively compete with kininogen for kallikrein binding (kd = 100 μmol/L). These results imply that D567-T591, a 25-residue peptide (HK25c), contains sufficient structural information for binding kallikrein in solution. D567-T591 also is the minimum structural sequence to block binding of kallikrein to HUVEC-bound HK (IC50 = 50 nmol/L) and to inhibit PK activation to kallikrein on the cell surface (IC50 = 80 nmol/L). In addition, D567-T591 also inhibits the generation of kallikrein-activated urokinase, which activates plasminogen to plasmin (IC50 = 100 nmol/L). Thus, HK-derived peptides may be useful compounds for modulating excessive fibrinolysis and hypotension in sepsis and multiple trauma.

scholarly journals Laminin γ3 Chain Binds to Nidogen and Is Located in Murine Basement Membranes

2005 ◽  
Vol 280 (23) ◽  
pp. 22146-22153 ◽  
Author(s):  
Nikolaus Gersdorff ◽  
Eddie Kohfeldt ◽  
Takako Sasaki ◽  
Rupert Timpl ◽  
Nicolai Miosge
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Self Assembly ◽  
Mammalian Cells ◽  
Polyclonal Antibodies ◽  
Basement Membranes ◽  
Electron Microscopic ◽  
Immunogold Staining ◽  
Adult Mice ◽  
Epidermal Growth

Recently a novel laminin γ3 chain was identified in mouse and human and shown to have the same modular structure as the laminin γ1 chain. We expressed two fragments of the γ3 chain in mammalian cells recombinantly. The first, domain VI/V, consisting of laminin N-terminal (domain VI) and four laminin-type epidermal growth factor-like (domain V) and laminin N-terminal modules, was shown to be essential for self-assembly of laminins. The other was domain III3–5, which consists of three laminin-type epidermal growth factor-like modules and is predicted to bind to nidogens. The γ3 VI/V fragment was a poor inhibitor for laminin-1 polymerization as was the β2 VI/V fragment. The γ3 III3–5 fragment bound to nidogen-1 and nidogen-2 with lower affinity than the γ1 III3–5 fragment. These data suggested that laminins containing the γ3 chain may assemble networks independent of other laminins. Polyclonal antibodies raised against γ3 VI/V and γ3 III3–5 showed no cross-reaction with homologous fragments from the γ1 and γ2 chains of laminin and allowed the establishment of γ chain-specific radioimmunoassays and light and electron microscopic immunostaining of tissues. This demonstrated a 20–100-fold lower content of the γ3 chain compared with the γ1 chain in various tissue extracts of adult mice. The expression of γ3 chain was highly tissue-specific. In contrast to earlier assumptions, the antibodies against the γ3 chain showed light microscopic staining exclusively in basement membrane zones of adult and embryonic tissues, such as the brain, kidney, skin, muscle, and testis. Ultrastructural immunogold staining localized the γ3 chain to basement membranes of these tissues.

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