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ILK, PINCH and parvin: the tIPP of integrin signalling

Nature Reviews Molecular Cell Biology volume 7, pages 20–31 (2006)Cite this article

Key Points

  • Adhesion of cells to the extracellular matrix (ECM) regulates processes that are related to cell survival, growth, differentiation, migration, polarity and proliferation. The main cell-surface receptors for ECM proteins are the integrins.

  • Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.

  • Numerous isoforms of PINCH and parvin coexist to allow for the formation of different IPP complexes. Differential binding partners for PINCH and parvin isoforms might impart distinct functions to each complex.

  • ILK has been identified as a Ser/Thr protein kinase in vitro. In vivo confirmation of kinase activity has proven difficult because mutations in ILK disrupt the assembly and function of the IPP complex.

  • Genetic deletion of ILK, PINCH and parvin isoforms reveals common functions that are related to cell adhesion, but subtle differences in knockout phenotypes indicate separable functions outside of focal adhesions.

Abstract

The ternary complex of integrin-linked kinase (ILK), PINCH and parvin functions as a signalling platform for integrins by interfacing with the actin cytoskeleton and many diverse signalling pathways. All these proteins have synergistic functions at focal adhesions, but recent work has indicated that these proteins might also have separate roles within a cell. They function as regulators of gene transcription or cell–cell adhesion.

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Figure 1: Biogenesis of focal adhesions.
Figure 2: Anatomy of the IPP complex and its binding partners.
Figure 3: Signalling through the IPP complex.
Figure 4: Divergence of the kinase domain of ILK.

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Acknowledgements

The authors acknowledge support from a Marie Curie International Fellowship within the 6th European Community Framework Programme to K.R.L, an Erwin Schroedinger fellowship from the Austrian Science Foundation (FWF) to O.K, and the Deutsche Forschungsgemeinschaft, Fonds der Chemischen Industrie and the Max-Planck Society. The authors would like to thank C. Zervas and members of the Fässler laboratory for critical reading of the manuscript.

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  1. Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsreid, 82152, Germany

    Kyle R. Legate, Eloi Montañez, Oliver Kudlacek & Reinhard Füssler

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DATABASES

Flybase

Dreadlocks

Misshapen

STCK

Interpro

LIM domain

PH domain

SH2 domain

SH3 domain

Swiss-Prot

AKT

ILK

kindlin-1

kindlin-2

NCK2

α-parvin

β-parvin

γ-parvin

PAT-4

paxillin

α-PIX

PINCH1

PINCH2

RSU1

TESK1

thymosin-β4

UNC-97

FURTHER INFORMATION

Reinhard Füssler's laboratory

Glossary

Extracellular matrix

(ECM). A network of secreted proteins and polysaccharides that surrounds all the connective tissues and underlines all the epithelial and the endothelial sheets. It provides a physical support for tissues, as well as a sink for the storage, release and presentation of growth factors.

Focal adhesion

A highly specialized cell-adhesion structure that connects actin filaments to the ECM through integrins. Immature focal adhesions are known as focal complexes, and those that are formed through interactions with fibronectin mature into structures known as fibrillar adhesions.

Ankyrin repeat

A protein–protein-interaction module that consists of approximately 30 amino acids. It was first identified in the yeast cell-cycle regulator Swi6/Cdc10 and the D. melanogaster signalling protein Notch, and it was named after the cytoskeletal protein ankyrin. This motif is found in more than 1,700 different proteins.

Pleckstrin homology (PH) domain

A phosphoinositide-binding motif that is composed of approximately 100 amino acids and is involved in receiving and transmitting signals at the interface between the membrane and cytosol.

Senescent

Cells that are undergoing a permanent form of cell-cycle arrest that was originally described for post-proliferative primary cells in culture. Senescence can be induced by DNA damage, oxidative stress, chemotherapy and excess mitogenic stimuli, and is controlled by the tumour suppressor proteins, p53 and retioblastoma protein.

LIM domain

A tandem cysteine-rich Zn2+-finger motif that mediates protein–protein interactions. It was originally identified in the transcription factors LIN11, ISL1 and MEC3.

Calponin homology (CH) domain

A relatively small motif that is present in several cytoskeletal proteins and functions as an actin-binding domain, especially when they are presented in tandem.

Small inhibitory RNA

(siRNA). Double-stranded RNA molecules of 21–25 nucleotides in length that are used as a viral defence mechanism and an endogenous gene-silencing mechanism from plants to humans.

Lamellipodium

Dynamic actin-mediated cell-membrane protrusions at the front of spreading and migrating cells. They are essential for cell motility, phagocytosis and the development of substrate adhesions.

RNA interference

(RNAi). A method to silence specific gene expression by introducing double-stranded RNA into the cell that matches the nucleotide sequence of the targeted mRNA.

LD motif

Leucine-rich protein-binding sequences with the consensus sequence LDXLLXXL.

Kindler syndrome

An inheritable epidermal defect that is characterized by blistering, abnormal pigmentation, fragile skin and increased cancer risk.

Thymosins

A large family of small peptides that was originally identified in the thymus, but is also found in many tissues. They are divided into three main groups: α-, β-, and γ-thymosins. β-Thymosins bind globular actin to maintain a pool of actin monomers in the cell.

Calpains

A superfamily of multimeric Ca2+-dependent cysteine proteases that is implicated in various cellular processes such as proliferation, differentiation and apoptosis. Deregulation of calpain activity has been implicated in various pathological conditions.

Sarcolemma

The plasma membrane that encloses striated muscle fibres.

Adherens junction

A highly specialized cell–cell-adhesion complex that contains cadherins and catenins, and which is connected to cytoplasmic actin filaments.

Dominant negative

Introduction of an inactive mutant gene product, which interferes with the functional endogenous gene product, perhaps by competing for available accessory factors.

Ataxia telangiectasia

(ATM). Autosomal recessive hereditary disease associated with DNA-repair defects and caused by mutations in the ATM (ataxia telangiectasia) gene. It is characterized by progressive cerebellar ataxia, dilation of blood vessels in the skin and eyes, chromosomal aberrations, immune dysfunction and an increased risk of cancer malignancy, particularly leukaemia and lymphoma.

PAT phenotype

A broad phenotypic class of lethal mutations that affect muscle formation in C. elegans. Mutations that cause a PAT (paralyzed and arrested elongation at twofold) phenotype, affect either components of the attachment complex or essential components within the sarcomere.

Dense bodies/M-lines

Focal-adhesion-like muscle-attachment structures in C. elegans. Dense bodies anchor actin filaments to the plasma membrane, and M-lines attach myosin filaments to the plasma membrane. Both structures are essential for the contractility and the maintenance of the muscles.

Dorsal closure

A mid-stage developmental process that involves the movement of lateral dorsal epithelia towards the dorsal midline. This process is required for the sealing of embryonic epidermis in D. melanogaster.

Podocyte

Highly specialized epithelial cells that cover the outer aspect of the glomerular basement membrane in the kidney. Mature podocytes possess a highly branched array of foot processes that are essential for glomerular filtration.

Chondrodysplasia

A heterogeneous group of genetic disorders, which are characterized by abnormal skeletal morphogenesis affecting the development and growth of most skeletal elements.

Inner cell mass

Inner cells of the blastocyst that retain pluripotency and give rise to all cell types of the future body.

Blastocyst

An early stage of embryonic development, during which cells begin to commit to developmental lineages.

Embryoid bodies

Three-dimensional spherical aggregates of differentiated cells that are derived from embryonic stem cells. The differentiation of embryoid bodies recapitulates many aspects of the early course of embryonic development in vivo.

Basement membrane

Specialized extracellular matrix that first appears during the peri-implantation stage in vertebrates and during gastrulation in invertebrates.

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Legate, K., Montañez, E., Kudlacek, O. et al. ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol 7, 20–31 (2006). https://doi.org/10.1038/nrm1789

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