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Edited by Barry Honig, Howard Hughes Medical Institute and Columbia University, New York, NY, and approved August 23, 2018 (received for review April 11, 2018)
Significance
Vertebrate cell growth, division, locomotion, morphogenesis, and development rely on the dynamic interactions of cells with extracellular matrix components via cell surface complexes termed focal adhesions that are composed of heterodimeric αβ integrin receptors, associated signaling molecules, and the large cytoskeletal protein talin. While it is known that talin activation and binding to β-integrin requires interactions with lipids, little is known regarding the structure and function of inactive vs. activated talin, and what is known is often disputed. Here we report that talin binding to the cell membrane seems necessary for integrin activation and focal adhesion formation, a finding that significantly advances our understanding of integrin activation and might aid the development of novel integrin therapeutic agents.
Abstract
Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding–deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin–cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding–deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.
Footnotes
- ↵1To whom correspondence should be addressed. Email: cmorrow{at}scripps.edu.
Author contributions: K.C., E.S.R., and T.I. designed research; K.C. and E.S.R. performed research; K.C., E.S.R., and T.I. analyzed data; and K.C., E.S.R., and T.I. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 6mfs).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1806275115/-/DCSupplemental.
Published under the PNAS license.
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The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation
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