The integrin superfamily of cell surface receptors includes may of the receptors for extracellular matrix components. Integrins have been implicated in many morphogenetic and differentiative events during embryogenesis, and a better understanding of integrin function will be crucial to understanding basic developmental processes, and therefore certain congenital defects, in humans. This proposal outlines a combined genetic, cellular and molecular biological approach to basic questions of integrin structure-function relationships. Using the PS integrins of Drosophila as our model system, the following lines of research will be pursued: 1. Mutations will be generated in the genes coding for the alpha and beta chains of the integrins. 2. The functions and protein associations of the integrins will be studied in situ, using clonal analysis, conditional alleles, and other genetic approaches. 3. A cell transformation system (in which integrin genes are introduced into and expressed in a cultured cell line) will be developed; this system will permit cell biological assays for specific integrin functions. 4. The functions of mutant integrins will be examined in the transformed cell lines, and the molecular bases of the mutations will be examined in the transformed cell lines, and the molecular bases of the mutations will be determined by sequencing. 5. The transformation system will be used in combination with in vitro mutagenesis to produce integrins with specific functional defects. These mutants can then be introduced into whole files, where their developmental consequences can be determined.

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National Institute of General Medical Sciences (NIGMS)
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Pathobiochemistry Study Section (PBC)
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University of Arizona
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Syed, Aleem; Arora, Neha; Bunch, Thomas A et al. (2016) The role of a conserved membrane proximal cysteine in altering ?PS2C?PS integrin diffusion. Phys Biol 13:066005
Kendall, Timmy; Mukai, Leona; Jannuzi, Alison L et al. (2011) Identification of integrin beta subunit mutations that alter affinity for extracellular matrix ligand. J Biol Chem 286:30981-93
Fraichard, Stephane; Bouge, Anne-Laure; Kendall, Timmy et al. (2010) Tenectin is a novel alphaPS2betaPS integrin ligand required for wing morphogenesis and male genital looping in Drosophila. Dev Biol 340:504-17
Bunch, Thomas A (2010) Integrin alphaIIbbeta3 activation in Chinese hamster ovary cells and platelets increases clustering rather than affinity. J Biol Chem 285:1841-9
Helsten, Teresa L; Bunch, Thomas A; Kato, Hisashi et al. (2008) Differences in regulation of Drosophila and vertebrate integrin affinity by talin. Mol Biol Cell 19:3589-98
Devenport, Danelle; Bunch, Thomas A; Bloor, James W et al. (2007) Mutations in the Drosophila alphaPS2 integrin subunit uncover new features of adhesion site assembly. Dev Biol 308:294-308
Smith, Emily A; Bunch, Thomas A; Brower, Danny L (2007) General in vivo assay for the study of integrin cell membrane receptor microclustering. Anal Chem 79:3142-7
James, Brian P; Bunch, Thomas A; Krishnamoorthy, Srinivasan et al. (2007) Nuclear localization of the ERK MAP kinase mediated by Drosophila alphaPS2betaPS integrin and importin-7. Mol Biol Cell 18:4190-9
Bunch, Thomas A; Kendall, Timmy L; Shakalya, Kishore et al. (2007) Modulation of ligand binding by alternative splicing of the alphaPS2 integrin subunit. J Cell Biochem 102:211-23
Subramanian, Arul; Wayburn, Bess; Bunch, Thomas et al. (2007) Thrombospondin-mediated adhesion is essential for the formation of the myotendinous junction in Drosophila. Development 134:1269-78

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