Structural and functional insights into PINCH LIM4 domain–mediated integrin signaling

Vėlyvis, Algirdas; Vaynberg, Julia; Yang, Yanwu; Vinogradova, Olga; Zhang, Yongjun; Wu, Chuanyue; Qin, Jun

doi:10.1038/nsb938

Cited by 67 publications

(46 citation statements)

References 38 publications

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“…It is increasingly clear that the interaction between PINCH-1 and Nck-2 is involved in regulation of actin cytoskeleton remodeling (25,26,28,38,39). It has not been determined, however, whether or not the binding of PINCH-1 to Nck-2 plays a role in PINCH-1-mediated cell survival signaling.…”

Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

“…The Nck-2 Binding Is Dispensable for PINCH-1-mediated Cell Survival Signaling-In addition to interacting with ILK through the N-terminal-most LIM1 domain, PINCH-1 interacts with Nck-2, an SH2/SH3-containing adaptor protein, via its C-terminal LIM4 domain (25,26). It is increasingly clear that the interaction between PINCH-1 and Nck-2 is involved in regulation of actin cytoskeleton remodeling (25,26,28,38,39).…”

Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

“…It has not been determined, however, whether or not the binding of PINCH-1 to Nck-2 plays a role in PINCH-1-mediated cell survival signaling. To test this we expressed a Nck-2 binding-defective PINCH-1 mutant (RRAA) in which Arg-197-Arg-198, located at the Nck-2 binding interface (26), were replaced with alanine residues in PINCH-1 knockdown cells (Fig. 2D, lanes 5 and 6).…”

Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

“…In addition, PINCH-1 interacts with Nck-2 (25, 26), an SH2/SH3-containing adaptor protein that is involved in both cell adhesion-and growth factormediated signaling and actin cytoskeleton remodeling (27-29). The Nck-2-binding site is located in the first zinc finger of the PINCH-1 C-terminal LIM4 domain (25,26). Recently, we have suppressed the expression of PINCH-1 and ILK, respectively, in mammalian cells using RNA interference.…”

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Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

Fukuda

et al. 2005

Journal of Biological Chemistry

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How cells couple and uncouple regulation of cellular processes such as shape change and survival is an important question in molecular cell biology. PINCH-1, a widely expressed protein consisting of five LIM domains and a C-terminal tail, is an essential focal adhesion protein with multiple functions including regulation of the integrin-linked kinase (ILK) level, cell shape, and survival signaling. We show here that the LIM1-mediated interaction with ILK regulates all these three processes. By contrast, the LIM4-mediated interaction with Nck-2, which regulates cell morphology and migration, is not required for the control of the ILK level and survival. Remarkably, a short 15-residue tail C-terminal to LIM5 is required for both cell shape modulation and survival, albeit it is not required for the control of the ILK level. The C-terminal tail not only regulates PINCH-1 localization to focal adhesions but also functions after it localizes there. These findings suggest that PINCH-1 functions as a molecular platform for coupling and uncoupling diverse cellular processes via overlapping but yet distinct domain interactions. Cell-extracellular matrix (ECM)1 adhesion is a fundamental process that is critically involved in embryonic development and numerous physiological and pathological processes including injury repair, cancer, and organ (e.g. heart and renal) failure. Among key regulators of cell-ECM adhesion and signaling are proteins localized at the membrane-actin cytoskeleton junctions in cell-ECM contacts (e.g. focal adhesions). PINCH-1 is a widely expressed focal adhesion protein consisting of five LIM domains and a short residue C-terminal tail (for review, see Refs. 1-4). Recent biochemical, cell biological, and genetic studies have demonstrated that PINCH-1 is crucial for cell shape modulation and signal transduction (5-13). Furthermore, there is evidence suggesting that PINCH-1 could serve as a useful target for therapeutic intervention of human diseases such as cancer and organ (e.g. heart and renal) failure (2, 4, 14 -19). Elucidating the molecular mechanism whereby PINCH-1 functions, therefore, is important for understanding the general principle that governs the regulation of cell-ECM adhesion and signaling as well as for the development of new therapeutic approaches that control these processes.PINCH-1 interacts with ILK (5, 20, 21), an equally widely expressed focal adhesion component that is essential for integrin-mediated cell-ECM adhesion and signaling (for review, see Refs. 2-4, 22, and 23). The ILK-binding site has been mapped to the second zinc finger of the N-terminal-most LIM1 domain that contains 21,24). In addition, PINCH-1 interacts with Nck-2 (25, 26), an SH2/SH3-containing adaptor protein that is involved in both cell adhesion-and growth factormediated signaling and actin cytoskeleton remodeling (27-29). The Nck-2-binding site is located in the first zinc finger of the PINCH-1 C-terminal LIM4 domain (25,26). Recently, we have suppressed the expression of PINCH-1 and ILK, respectively, in ...

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Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

Section: Pinch-1 Functions In the Maintenance Of The Ilk Proteinmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

Fukuda

et al. 2005

Journal of Biological Chemistry

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“…Additional examples of protein-binding modules that exhibit recognition of distinct targets have been previously reported. 5,6 The Itk SH2 domain represents the first example of dual ligand recognition controlled by proline cis/trans isomerization within the receptor. Given the intrinsic nature of proline isomerization and the modest energy barrier between conformers, proline cis/trans isomerization may be a general mechanism allowing for diversity in protein recognition.…”

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Ligand Specificity Modulated by Prolyl Imide Bond Cis/Trans Isomerization in the Itk SH2 Domain: A Quantitative NMR Study

et al. 2003

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Zinc Enzymes

Auld

2005

Encyclopedia of Inorganic Chemistry

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A remarkable mosaic of zinc‐binding motifs influence the function of proteins involved in all aspects of metabolism, providing evidence on the molecular level for the indispensability of zinc to growth and development and transmission of the genetic message. There are now about 400 three‐dimensional structures for zinc proteins, representing all six classes of enzymes and covering a wide range of phyla and species. These structures provide standards of reference for the identity and nature of zinc ligands in other proteins for which only the primary structure is known. Three primary types of zinc sites are apparent from examination of these structures: structural, catalytic, and cocatalytic. The most common amino acids that supply ligands to these sites are His, Glu, Asp, and Cys. In catalytic sites, zinc generally forms complexes with water and any three nitrogen, oxygen, and sulfur donors with His being the predominant amino acid chosen. Water is always a ligand to such sites. Structural zinc sites have four protein ligands and no bound water molecule. Twelve of the twenty‐two permutations of four Cys, His, Glu, and Asp ligands have been observed. Cys is the preferred ligand in such sites. Cocatalytic sites contain two or three metals in close proximity with two of the metals bridged by a side‐chain moiety of a single amino acid residue, such as Asp, Glu, or His and sometimes a water molecule. Asp and His are the preferred amino acids for these sites. The properties of both H‐bonding and hydrophobic amino acid ‘outer shell ligands’ and the secondary support structure of the zinc sites is important to the function, stability, and reactivity of the bound metal. The influence of zinc on quaternary protein structure has led to the identification of a fourth type of zinc‐binding site, protein interface. In this case, zinc sites are formed from ligands supplied from amino acid residues residing in the binding surface of two proteins. The resulting zinc site usually has the coordination properties of a catalytic or structural zinc‐binding site.

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Structural and functional insights into PINCH LIM4 domain–mediated integrin signaling

Cited by 67 publications

References 38 publications

Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

Ligand Specificity Modulated by Prolyl Imide Bond Cis/Trans Isomerization in the Itk SH2 Domain: A Quantitative NMR Study

Zinc Enzymes

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