Skeletal muscle is an ideal system with which to study adhesion molecules and the membrane-cytoskeletal linkages in which they participate as they play a central role in muscle development, structure and physiology, and pathology. Once muscle precursors have migrated to their targets, the program of terminal differentiation commences, which is regulated by the extracellular matrix. An elaborate contractile apparatus is synthesized and organized, which contains several cell surface associations including the myotendinous and costomeric junctions. Muscle cells are innervated at neuromuscular junctions. It is now clear that dystrophin, the muscular dystrophy gene product, has homologies to cytoskeletal proteins and is associated with adhesion molecules like integrin. The integrin family of receptors for extracellular matrix molecules are implicated in all of the above phenomena by virtue of their localization in junctional regions, their functions as dual receptors for extracellular matrix and cytoskeletal molecules, and as mediators of signal transductions. The hypothesis that guides our current research is that the integrins play a central role in organizing the surface, the extracellular matrix, and the contractile apparatus of skeletal muscle and in addition mediate signals from the extracellular matrix triggering its differentiation. Our general aims for the project period are to identify and characterize the amino acid sequences on integrin cytoplasmic and extracellular domains that determine the organization of junctional regions and determine their role in adhesion. This will be done using a recently constructed library of single-amino acid substitutions in the Beta1- cytoplasmic domain and synthetic peptides corresponding to active and mutant sequences. A similar library will be constructed for alpha subunits. Analogous, but different, methods are proposed to find extracellular matrix binding sequences in the extracellular domain. The second major aim is to identify and purify novel integrin associated cytoplasmic proteins. Previous specificity problems will be addressed using peptide sequences derived from mutant and wild type cytoplasmic domain sequences. Recently we have identified two novel integrin associated molecules. Both are cytoskeletal and one is a complex of 5 proteins. They will be characterized further for binding specificities and localization on muscle. The third objective is to elucidate the role of integrins in organizing and stabilizing junctional regions. This will be done using molecular genetic techniques to identify functional domains, alter regulation of expression, and reduce or eliminate the expression of specific integrins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37GM023244-18
Application #
3484452
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1988-01-01
Project End
1997-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
18
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Bachir, Alexia I; Horwitz, Alan Rick; Nelson, W James et al. (2017) Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells. Cold Spring Harb Perspect Biol 9:
Martin-Vilchez, Samuel; Whitmore, Leanna; Asmussen, Hannelore et al. (2017) RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development. PLoS One 12:e0170464
Cross, A M; Wilson, A L; Guerrero, M S et al. (2016) Breast cancer antiestrogen resistance 3-p130(Cas) interactions promote adhesion disassembly and invasion in breast cancer cells. Oncogene 35:5850-5859
Ramos, Grasieli de Oliveira; Bernardi, Lisiane; Lauxen, Isabel et al. (2016) Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma. PLoS One 11:e0151338
Newell-Litwa, Karen A; Badoual, Mathilde; Asmussen, Hannelore et al. (2015) ROCK1 and 2 differentially regulate actomyosin organization to drive cell and synaptic polarity. J Cell Biol 210:225-42
Newell-Litwa, Karen A; Horwitz, Rick; Lamers, Marcelo L (2015) Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Dis Model Mech 8:1495-515
Juanes-Garcia, Alba; Chapman, Jessica R; Aguilar-Cuenca, Rocio et al. (2015) A regulatory motif in nonmuscle myosin II-B regulates its role in migratory front-back polarity. J Cell Biol 209:23-32
Hodges, Jennifer L; Vilchez, Samuel Martin; Asmussen, Hannelore et al. (2014) ?-Actinin-2 mediates spine morphology and assembly of the post-synaptic density in hippocampal neurons. PLoS One 9:e101770
Potvin-Trottier, Laurent; Chen, Lingfeng; Horwitz, Alan Rick et al. (2013) A nu-space for ICS: characterization and application to measure protein transport in live cells. New J Phys 15:
Tejera, Emilio; Rocha-Perugini, Vera; López-Martín, Soraya et al. (2013) CD81 regulates cell migration through its association with Rac GTPase. Mol Biol Cell 24:261-73

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