Life Sciences & Biotechnology
Title : | Molecular analysis of interacting residues necessary for ILK-PINCH-Parvin (IPP) complex formation mediating integrin signalling at the musculoskeletal junction |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Benazir Fatma, Central University Of Jharkhand |
Timeline Start Year : | 2022 |
Timeline End Year : | 2024 |
Contact info : | benazirfatma07@gmail.com |
Details
Executive Summary : | Aberration in cell-matrix adhesions would lead to dysfunction in embryogenesis, homeostasis and remodelling of tissues and organs leading to biological dysfunctions including musculoskeletal disorder. A triad of Integrin linked kinase (ILK), PINCH (cysteine-histidine-rich protein), and parvin commonly known as IPP complex helps in the regulation of the maturation of cell-matrix adhesions. The IPP complex mediates the integrin-actin crosstalk at Drosophila embryo muscle attachment sites (MASs). ILK an important member of IPP complex, deficiency has been linked to muscular dystrophy. Skeletal muscles dysfunction in mice upon ILK deletion has been reported. In the absence of ILK, destabilization of PINCH and parvin proteins was observed which disrupted their recruitment to the MAS causing the loss of IPP-complex formation. PINCH too is actively involved in the proper cytoskeletal organization and ECM adhesion. PINCH lacks catalytic abilities, nevertheless it plays an important role by serving as an important link between integrins and downstream signalling pathways in the IPP complex triggering cell migration. Impaired PINCH can cause diverse array of diseases including renal failure, cardiomyopathy, nervous system degeneration and demyelination, and tumorigenesis. Parvin, an actin binding protein in the IPP triad too plays an important role in focal contacts. Parvin in Drosophila resembles 59%, 57% and 42% with human β-, α- and γ-parvin respectively. Mutational studies on Drosophila parvin have shown muscular defects which was restored by moderately expressing a wild -type parvin transgene in somatic muscles and tendon cells suggesting that parvin possesses indispensable functions in these tissues.
The molecular mechanisms behind the assembly, regulations, and functions of the IPP complexes remains elusive even though recent studies have determined that the IPP complexes explain important physical linkages between actin and integrins, and transduce diverse signals from ECM to intracellular effectors. Studies are yet to be done on multiple cellular processes unearthing additional partners of IPP complexes, molecular residues important in complex formation and the role of IPP in, cell-ECM adhesion/signalling, deregulation of which leads to pathogenesis of diseases. The interaction of Rsu1 with PINCH also suggests the possibility of existence of quadripartite complex instead of the tripartite IPP complex. Differential IPP complex domains contributed by its members may be selectively important for interaction with a specific class of focal adhesion proteins including integrins. The aim of the proposed work is to identify the novel interactors of IPP complex and molecular residues facilitating the interaction This study will further give insight on the muscle phenotype due to assembly of mutant IPP complex in the Drosophila melanogaster. Overall, the project aims to elucidate IPP complex role in muscle development and function in Drosophila. |
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