2 research outputs found
Structure/Function Analysis of Type IIa Receptor Tyrosine Phosphatases on Drosophila Muscle Integrity
Title from PDF of title page viewed September 20, 2019Dissertation advisor: Samuel BouyainVitaIncludes bibliographical references (pages 115-126)Thesis (Ph.D.)--School of Biological Sciences. University of Missouri--Kansas City, 2018The Lar-family of receptor protein tyrosine phosphatases (RPTPs); including
Lar, RPTPσ and RPTPδ, are utilized in signal transduction pathways during neural
development. Fundamentally, the processes of axon guidance and synaptogenesis are
carried out by rearrangements of the actin cytoskeleton for extension and maturation of
structures. To determine whether this regulation is conserved in other tissues, we
utilized interdisciplinary approaches for a structure/function analysis of Lar-RPTPs in
the Drosophila musculature. We find that the single fly ortholog, Dlar, is localized to
the muscle costamere in wandering L3 larvae. The costamere has important functions
in muscle integrity and force transmission during contractions. Further, depletion of
Dlar in the musculature causes aberrant sarcomeric actin patterning and mislocalization
of the major transmembrane receptor of the costamere, integrin dimers. Ablation of two
additional proteins from the musculature; including the guanine nucleotide exchange
factor, Trio, and the basement membrane protein, Glutactin (Glt), results in similar
disruptions to the muscle architecture. Thus, Trio and Glt provide links to actin through
the Rho family of small GTPases and the BM membrane which is intimately involved
in integrin signaling. We show that the actin cytoskeletal aberrations cause deficits in
larval locomotor function. Additionally, we find that the cytosolic domains of Dlar are
particularly important for muscle function and have implications in integrin signaling
versus physical receptor/ligand interactions which agree with x-ray crystallographic
analysis of the FN4-6 repeats. A proteomic approach was utilized to find novel binding
partners and resulted in identification of basement membrane proteins as conserved
Lar-RPTP ligands. Finally, we offer a model for Dlar signaling that results in the low
affinity integrin conformation induced by inside-out signals arising from actin
remodeling.Introduction -- Materials and methods -- Genetic investigation of DLAR function in muscle tissue - Structural analysis of RPTP type IIA FN domains 4-6 -- Detecting physical interactions of LAR-RPTPS -- Final discussion -- Appendi