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A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted.

ABSTRACT: PINCH, integrin-linked kinase (ILK) and Ras suppressor-1 (RSU-1) are molecular scaffolding proteins that form a physical complex downstream of integrins, and have overlapping roles in cellular adhesion. In Drosophila, PINCH and ILK colocalize in cells and have indistinguishable functions in maintaining wing adhesion and integrin to actin linkage in the muscle. We sought to determine whether the direct physical interaction between PINCH and ILK was essential for their functions using transgenic flies expressing a version of PINCH with a point mutation that disrupts ILK binding (PINCH(Q38A)). We demonstrate that the PINCH-ILK interaction is not required for viability, for integrin-mediated adhesion of the wing or muscle, or for maintaining appropriate localization or levels of either PINCH or ILK. These results suggest alternative modes for PINCH localization, stabilization and linkage to the actin cytoskeleton that are independent of a direct interaction with ILK. Furthermore, we identified a synthetic lethality in flies carrying both the PINCH(Q38A) mutation and a null mutation in the gene encoding RSU-1. This lethality does not result from PINCH mislocalization or destabilization, and illustrates a novel compensatory role for RSU-1 in maintaining viability in flies with compromised PINCH-ILK binding. Taken together, this work highlights the existence of redundant mechanisms in adhesion complex assembly that support integrin function in vivo.

SUBMITTER: Elias MC

PROVIDER: S-EPMC3434853 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted.

Elias Maria C MC Pronovost Stephen M SM Cahill Kinley J KJ Beckerle Mary C MC Kadrmas Julie L JL

Journal of cell science 20120330 Pt 13

PINCH, integrin-linked kinase (ILK) and Ras suppressor-1 (RSU-1) are molecular scaffolding proteins that form a physical complex downstream of integrins, and have overlapping roles in cellular adhesion. In Drosophila, PINCH and ILK colocalize in cells and have indistinguishable functions in maintaining wing adhesion and integrin to actin linkage in the muscle. We sought to determine whether the direct physical interaction between PINCH and ILK was essential for their functions using transgenic f ...[more]

PMID: 22467865

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Project description:Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype.

Dataset Information

A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted.

Publications

A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted.

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