更新于：2024-11-01

laminin x UTRN

更新于：2024-11-01

基本信息

关联

项与 laminin x UTRN 相关的药物

LAM-211

靶点

UTRN x laminin

作用机制

UTRN调节剂 [+1]

在研机构-

原研机构

Prothelia, Inc.

在研适应症-

非在研适应症

杜氏肌营养不良症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 laminin x UTRN 相关的临床结果

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100 项与 laminin x UTRN 相关的转化医学

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0 项与 laminin x UTRN 相关的专利（医药）

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项与 laminin x UTRN 相关的文献（医药）

2022-03-03·Human Molecular Genetics

Sarcospan increases laminin-binding capacity of α-dystroglycan to ameliorate DMD independent of Galgt2

Article

作者: Stark, Rachelle L ; Crosbie, Rachelle H ; Beedle, Aaron M ; Shin, Kara M ; Mamsa, Hafsa

AbstractIn Duchenne muscular dystrophy (DMD), mutations in dystrophin result in a loss of the dystrophin-glycoprotein complex (DGC) at the myofiber membrane, which functions to connect the extracellular matrix with the intracellular actin cytoskeleton. The dystroglycan subcomplex interacts with dystrophin and spans the sarcolemma where its extensive carbohydrates (matriglycan and CT2 glycan) directly interact with the extracellular matrix. In the current manuscript, we show that sarcospan overexpression enhances the laminin-binding capacity of dystroglycan in DMD muscle by increasing matriglycan glycosylation of α-dystroglycan. Furthermore, we find that this modification is not affected by loss of Galgt2, a glycotransferase, which catalyzes the CT2 glycan. Our findings reveal that the matriglycan carbohydrates, and not the CT2 glycan, are necessary for sarcospan-mediated amelioration of DMD. Overexpression of Galgt2 in the DMD mdx murine model prevents muscle pathology by increasing CT2 modified α-dystroglycan. Galgt2 also increases expression of utrophin, which compensates for the loss of dystrophin in DMD muscle. We found that combined loss of Galgt2 and dystrophin reduced utrophin expression; however, it did not interfere with sarcospan rescue of disease. These data reveal a partial dependence of sarcospan on Galgt2 for utrophin upregulation. In addition, sarcospan alters the cross-talk between the adhesion complexes by decreasing the association of integrin β1D with dystroglycan complexes. In conclusion, sarcospan functions to re-wire the cell to matrix connections by strengthening the cellular adhesion and signaling, which, in turn, increases the resilience of the myofiber membrane.

2021-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease2区 · 生物学

Biochemical and biomechanical characteristics of dystrophin-deficient mdx mouse lens

2区 · 生物学

Article

作者: Karnam, Shruthi ; Rao, Ponugoti V ; Skiba, Nikolai P

The molecular and cellular basis for cataract development in mice lacking dystrophin, a scaffolding protein that links the cytoskeleton to the extracellular matrix, is poorly understood. In this study, we characterized lenses derived from the dystrophin-deficient mdx^3cv mouse model. Expression of Dp71, a predominant isoform of dystrophin in the lens, was induced during lens fiber cell differentiation. Dp71 was found to co-distribute with dystroglycan, connexin-50 and 46, aquaporin-0, and NrCAM as a large cluster at the center of long arms of the hexagonal fibers. Although mdx^3cv mouse lenses exhibited dramatically reduced levels of Dp71, only older lenses revealed punctate nuclear opacities compared to littermate wild type (WT) lenses. The levels of dystroglycan, syntrophin, and dystrobrevin which comprise the dystrophin-associated protein complex (DAPC), and NrCAM, connexin-50, and aquaporin-0, were significantly lower in the lens membrane fraction of adult mdx^3cv mice compared to WT mice. Additionally, decreases were observed in myosin light chain phosphorylation and lens stiffness together with a significant elevation in the levels of utrophin, a functional homolog of dystrophin in mdx^3cv mouse lenses compared to WT lenses. The levels of perlecan and laminin (ligands of α-dystroglycan) remained normal in dystrophin-deficient lens fibers. Taken together, although mdx^3cv mouse lenses exhibit only minor defects in lens clarity possibly due to a compensatory increase in utrophin, the noted disruptions of DAPC, stability, and organization of membrane integral proteins of fibers, and stiffness of mdx^3cv lenses reveal the importance of dystrophin and DAPC in maintaining lens clarity and function.

2019-02-01·Molecular & Cellular Proteomics1区 · 生物学

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

1区 · 生物学

Article

作者: Myllymäki, Satu-Marja ; Vuorela, Mikko ; Kämäräinen, Ulla-Reetta ; Varjosalo, Markku ; Manninen, Aki ; Miettinen, Sini ; Liu, Xiaonan ; Cruz, Sara Pereira

Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have used proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia-specific β4-integrin that, as α6β4-heterodimer, forms the core of HDs. The analysis identified ∼150 proteins that were specifically labeled by BirA-tagged integrin-β4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-β4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate β4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, although establishment of functional HDs depends on the formation of α6β4-heterodimers, the assembly of β4-interactome was not strictly dependent on α6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the β4-integrin.