The 37/67-kDa laminin receptor (LAMR/RPSA) is a remarkably multifaceted protein with functions associated with a diverse array of fundamental cellular processes. Crucially integrated into laminin binding, ribosome biogenesis, cytoskeleton reorganization and chromatin interactions, LAMR governs cellular processes the likes of growth, survival, protein synthesis, extracellular matrix adhesion, migration and differentiation. This repertoire of activity unsurprisingly links LAMR to a number of pathologies. Metastatic cancer, neurodegenerative disease, developmental defects and microbial infection have all have been associated with altered behavior of this vital protein. Clearly a molecule of great physiological relevance, LAMR presents an appealing therapeutic target.
This work describes the identification of a druggable site within the LAMR structure and the discovery of small molecules that block the interaction of LAMR with laminin. Derivatives of this small molecule prevent cellular migration, substantially attenuate protein synthesis and may partially block tumor cell implantation in a murine model of metastasis. Several details about the nature of LAMR-laminin binding and the involvement of the intrinsically disordered C-terminus are also described in addition to the identification of a SUMO modified LAMR species, 53-kDa LAMR. Development of effective LAMR inhibitors could lead to small molecules useful in combating a variety of pathology associated functions.
|Commitee:||Cho, Hearn J., Gold, Leslie I., Hubbard, Stevan R., Zagzag, David|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 76/01(E), Dissertation Abstracts International|
|Keywords:||Druggable sites, Laminin receptors, Small molecule inhibitors, Therapeutic targets|
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