Integrin Structure, Allostery, and Bidirectional Signaling

Arnaout, M. Amin; Mahalingam, Bhuvaneshwari; Xiong, Jian-Ping

doi:10.1146/annurev.cellbio.21.090704.151217

Cited by 488 publications

(463 citation statements)

References 127 publications

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“…The LM2/1 antibody recognizes the CD11b I domain (or Adomain), which is where most endogenous Mac-1 ligands bind through a metal ion-dependent adhesion site (MIDAS) (23). We hypothesized, based on the LM2/1 blocking data, that the I domain of CD11b is required for LukAB-mediated killing of target cells.…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

DuMont

Yoong

Day

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

193

279

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Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and celltype specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin's tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.toxin receptor | pore-forming cytotoxin

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Section: Resultsmentioning

confidence: 99%

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

DuMont

Yoong

Day

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

193

279

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show abstract

“…The integrin PSI domain has been characterized for regulatory activity (20)(21)(22). Given our results, we hypothesized that this domain might also function as a ligandreceptor binding site in ␤ 1 integrins and set out to purify extracellular proteins that might bind to this region.…”

Section: A Cytoplasmic Adapter Serves As a Receptor For The Psi Domaimentioning

confidence: 93%

An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment

Mintz

Cardó-Vila

Ozawa

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian cell membranes provide an interface between the intracellular and extracellular compartments. It is currently thought that cytoplasmic signaling adapter proteins play no functional role within the extracellular tumor environment. Here, by selecting combinatorial random peptide libraries in tumor-bearing mice, we uncovered a direct, specific, and functional interaction between CRKL, an adapter protein [with Src homology 2 (SH2)-and SH3-containing domains], and the plexin-semaphorin-integrin domain of ␤1 integrin in the extracellular milieu. Through assays in vitro, in cellulo, and in vivo, we show that this unconventional and as yet unrecognized proteinprotein interaction between a regulatory integrin domain (rather than a ligand-binding one) and an intracellular adapter (acting outside of the cells) triggers an alternative integrin-mediated cascade for cell growth and survival. Based on these data, here we propose that a secreted form of the SH3/SH2 adaptor protein CRKL may act as a growth-promoting factor driving tumorigenesis and may lead to the development of cancer therapeutics targeting secreted CRKL.cancer ͉ CrkL ͉ integrin ͉ phage display C ell membranes have evolved as a tight and compartmentalized, but dynamic, interface between intracellular and extracellular contents (1, 2). To maintain such homeostasis, transmembrane receptors mediate bidirectional signaling across the cell surface through a complex spatial and temporal organization (3, 4). Thus, protein location in signal transduction is central to specificity of cellular responses (2,5,6). For example, cell surface receptors such as integrins undergo conformational changes elicited through ligand binding to enable a cross-talk with signal transduction cascades such as the MAPK pathways; conventional integrin ligands include ECM proteins that recognize integrin extracellular domains and cytoskeletal proteins that interact with intracellular domains (3-4, 7-9).To gain insight into signal transduction across cell membranes in cancer, we set out to identify functional protein interactions in a tumor xenograft model; we reasoned that a combinatorial approach (10-14) in vivo might provide clues by emulating ligand-receptor binding in the context of the tumor microenvironment. Here, we show a specific interaction between the intracellular signaling protein CRKL and a regulatory (rather than ligand-binding) ␤ 1 integrin extracellular domain. Surprisingly, we found that CRKL targets the plexin-semaphorin-integrin (PSI) domain of ␤ 1 integrin chain located outside of the cell and promotes cell growth and survival. These results indicate an unrecognized integrin-mediated outside-in function for intracellular mediators, such as Src homology 2 (SH2)-and SH3-containing proteins, in activating proliferative pathways. Results Combinatorial Selection in Vivo Yields Tumor-Homing Peptides.We administered a phage library (12,14,15) i.v. into nu/nu (nude) mice bearing human DU145-derived prostate cancer xenografts and recovered tumors after 24-h circulation. ...

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“…However, recent work has clearly identified signalling molecules that associate with integrins. Many studies have focused on the short cytoplasmic tails and the transmembrane domains of the integrin α and β subunits (Box 1, panel a), which may have applications in future anti-integrin strategies [103][104][105] .…”

Section: Integrin Signallingmentioning

confidence: 99%

“…Potential strategies are focused on the short cytoplasmic tails of the integrin α and β subunits, although there is also evidence that the transmembrane domains may play a role [103][104]166 .…”

Section: Receptor Antagonists That Do Not Induce Conformational Changmentioning

confidence: 99%

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

411

350

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Integrin Structure, Allostery, and Bidirectional Signaling

Cited by 488 publications

References 127 publications

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment

Integrins as therapeutic targets: lessons and opportunities

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