Nischarin, a novel protein that interacts with the integrin alpha5 subunit and inhibits cell migration.
Integrins have been implicated in key cellular functions, including cytoskeletal organization, motility, growth, survival, and control of gene expression. The plethora of integrin alpha and beta subunits suggests that individual integrins have unique biological roles, implying specific molecular connections between integrins and intracellular signaling or regulatory pathways. Here, we have used a yeast two-hybrid screen to identify a novel protein, termed Nischarin, that binds preferentially to the cytoplasmic domain of the integrin alpha5 subunit, inhibits cell motility, and alters actin filament organization. Nischarin is primarily a cytosolic protein, but clearly associates with alpha5beta1, as demonstrated by coimmunoprecipitation. Overexpression of Nischarin markedly reduces alpha5beta1-dependent cell migration in several cell types. Rat embryo fibroblasts transfected with Nischarin constructs have "basket-like" networks of peripheral actin filaments, rather than typical stress fibers. These observations suggest that Nischarin might affect signaling to the cytoskeleton regulated by Rho-family GTPases. In support of this, Nischarin expression reverses the effect of Rac on lamellipodia formation and selectively inhibits Rac-mediated activation of the c-fos promoter. Thus, Nischarin may play a negative role in cell migration by antagonizing the actions of Rac on cytoskeletal organization and cell movement.
Alahari
S K
SK
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. alahari@med.unc.edu
Lee
J W
JW
Juliano
R L
RL
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D016466:CHO Cells; D002451:Cell Compartmentation; D002465:Cell Movement / Q000502:physiology*; D006224:Cricetinae; D003599:Cytoskeleton / Q000648:ultrastructure; D015723:Gene Library; D054755:Imidazoline Receptors; D039482:Integrin alpha5; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D015703:Antigens, CD; D054755:Imidazoline Receptors; D039482:Integrin alpha5; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; C503041:Nisch protein, mouse; D011506:Proteins; D020744:rac GTP-Binding Proteins