<i>Drosophila</i> Integrin-Linked Kinase Is Required at Sites of Integrin Adhesion to Link the Cytoskeleton to the Plasma Membrane

Zervas, Christos G.; Gregory, Stephen L.; Brown, Nicholas H.

doi:10.1083/jcb.152.5.1007

Cited by 262 publications

(304 citation statements)

References 61 publications

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“…Because both PINCH and ILK have been shown to be required for muscle structure and function in Drosophila (Zervas et al, 2001;Clark et al, 2003), we performed high-resolution fluorescence microscopy to evaluate the integrity of actinmembrane linkages in PINCH Q38A -Flag rescued flies. The Drosophila embryonic somatic muscle consists of segments of muscle fibers, where two muscle segments meet specialized tendon cells that are part of the epidermis (Bökel and Brown, 2002;Brower, 2003;Schweitzer et al, 2010).…”

Section: Ilk-pinch-rsu-1 Adhesion Complexes 3187mentioning

confidence: 99%

“…Null mutations that eliminate either PINCH (encoded by the steamer duck gene, stck) or ILK (encoded by the ilk gene) result in late embryonic or early larval lethality, and homozygous mutant clones of either gene in the wing result in wing blisters similar to what is observed when integrin function is compromised (Brower and Jaffe, 1989;Brabant et al, 1996;Zervas et al, 2001;Clark et al, 2003). PINCH and ILK colocalize at muscle attachment sites in the Drosophila embryo and both proteins are required to maintain the attachment of actin filaments to integrin-rich membrane domains (Zervas et al, 2001;Clark et al, 2003). In contrast, other integrin effectors, including rhea (Talin) and wech, are required for integrindependent anchorage of the cell membrane to the extracellular matrix Löer et al, 2008).…”

Section: Introductionmentioning

confidence: 96%

“…Genetic analysis has revealed that several cytoplasmic factors, including PINCH (particularly interesting cysteine-histidine-rich protein) and ILK (integrin-linked kinase), are required to support integrin-mediated adhesion in vivo (Prout et al, 1997;Walsh and Brown, 1998;Zervas et al, 2001;Löer et al, 2008). Null mutations that eliminate either PINCH (encoded by the steamer duck gene, stck) or ILK (encoded by the ilk gene) result in late embryonic or early larval lethality, and homozygous mutant clones of either gene in the wing result in wing blisters similar to what is observed when integrin function is compromised (Brower and Jaffe, 1989;Brabant et al, 1996;Zervas et al, 2001;Clark et al, 2003). PINCH and ILK colocalize at muscle attachment sites in the Drosophila embryo and both proteins are required to maintain the attachment of actin filaments to integrin-rich membrane domains (Zervas et al, 2001;Clark et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Elias

Pronovost

Cahill

et al. 2012

Journal of Cell Science

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Summary 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.

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Section: Ilk-pinch-rsu-1 Adhesion Complexes 3187mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Elias

Pronovost

Cahill

et al. 2012

Journal of Cell Science

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“…20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells.…”

mentioning

confidence: 99%

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

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“…In contrast to vertebrate ILK, Drosophila ILK does not bind directly to integrin, and does not require an active kinase domain, as a kinase-dead version of ILK can fully rescue the mutant phenotype (Zervas et al, 2001). ILK translocation to myotendious junctions also does not require PINCH (Clark et al, 2003), arguing that other mechanisms must be involved.…”

Section: Force and Sarcolemmal Adhesion Site Assemblymentioning

confidence: 94%

Molecular mechanisms of mechanosensing in muscle development

Jani

Schöck

2009

Developmental Dynamics

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Mechanical forces are crucial to muscle development and function, but the mechanisms by which forces are sensed and transduced remain elusive. Evidence implicates the sarcolemmal lattice of integrin adhesion and the Z-disk components of the contractile machinery in such processes. These mechanosensory devices report changes in force to other cellular compartments by self-remodeling. Here we explore how their structural and functional properties integrate to regulate muscle development and maintenance.

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Drosophila Integrin-Linked Kinase Is Required at Sites of Integrin Adhesion to Link the Cytoskeleton to the Plasma Membrane

Cited by 262 publications

References 61 publications

A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Molecular mechanisms of mechanosensing in muscle development

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