Integrin signalling at a glance

Harburger, David S.; Calderwood, David A.

doi:10.1242/jcs.018093

Cited by 779 publications

(530 citation statements)

References 57 publications

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“…In this context, deciphering the molecular mechanisms controlling integrin-dependent adhesion of normal hematopoietic and leukemia cells may ultimately lead to new treatment strategies that specifically target leukemia cells. Although players that activate integrins have been described, few players that inhibit integrins have been identified so far (38,39). Among them, FLNa has been proposed to compete with talin for binding to the cytoplasmic tail of integrin ␤ subunits (32).…”

Section: Discussionmentioning

confidence: 99%

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

Lamsoul

Burande

Razinia

et al. 2011

Journal of Biological Chemistry

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By providing contacts between hematopoietic cells and the bone marrow microenvironment, integrins are implicated in cell adhesion and thereby in control of cell fate of normal and leukemia cells. The ASB2 gene, initially identified as a retinoic acid responsive gene and a target of the promyelocytic leukemia retinoic acid receptor ␣ oncoprotein in acute promyelocytic leukemia cells, encodes two isoforms, a hematopoietic-type (ASB2␣) and a muscle-type (ASB2␤) that are involved in hematopoietic and myogenic differentiation, respectively. ASB2␣ is the specificity subunit of an E3 ubiquitin ligase complex that targets filamins to proteasomal degradation. To examine the relationship of the ASB2␣ structure to E3 ubiquitin ligase function, functional assays and molecular modeling were performed. We show that ASB2␣, through filamin A degradation, enhances adhesion of hematopoietic cells to fibronectin, the main ligand of ␤1 integrins. Furthermore, we demonstrate that a short N-terminal region specific to ASB2␣, together with ankyrin repeats 1 to 10, is necessary for association of ASB2␣ with filamin A. Importantly, the ASB2␣ N-terminal region comprises a 9-residue segment with predicted structural homology to the filamin-binding motifs of migfilin and ␤ integrins. Together, these data provide new insights into the molecular mechanisms of ASB2␣ binding to filamin.

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Section: Discussionmentioning

confidence: 99%

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

Lamsoul

Burande

Razinia

et al. 2011

Journal of Biological Chemistry

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“…Inversely, the binding of intracellular proteins such as talin and kindlin to the cytoplasmic tails of integrin triggers the conformational changes and activation of integrin, which is termed "inside-out signaling" [16]. The bidirectional signaling involves assembly and disassembly of numerous components that form around the cytoplasmic tail of integrins [17]. The adhesion complexes formed by integrin is known as "integrin adhesome", which consists of at least 156 components interlinked by hundreds of interactions [18,19].…”

Section: Overview Of Integrin Functions In Tumor Metastasismentioning

confidence: 99%

Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

Yue

Zhang

Chen

2012

Cancer Microenvironment

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The extracellular matrix (ECM) is an extracellular scaffold composed of complex mixtures of proteins that plays a pivotal role in tumor progression. ECM remodeling is crucial for tumor migration and invasion during the process of metastasis. ECM can be remodeled by several processes including synthesis, contraction and proteolytic degradation. In order to cross through the ECM barriers, malignant cells produce a spectrum of extracellular proteinases including matrix metalloproteinases (MMPs), serine proteases (mainly the urokinase plasminogen activator (uPA) system) and cysteine proteases to degrade ECM components. As major adhesion molecules to support cell attachment to ECM, integrins play critical roles in tumor progression by enhancing tumor cell survival, migration and invasion. Previous studies have shown that integrins can regulate the expression and activity of these proteases through different pathways. This review summarizes the roles of MMPs and uPA system in ECM remodeling and discusses the regulatory functions of integrins on these proteases in invasive tumors.

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“…However, the mechanisms responsible for the subsequent disengagement of LFA-1 from the IS remain elusive. In migrating cells, cleavage of talin or the integrin  tail by calpain, phosphorylation, or dephosphorylation events, and recruitment of competitors of talin binding to the integrin have been proposed as mechanisms by which the link between integrins and the actin cytoskeleton is disrupted (Calderwood, 2004;Harburger and Calderwood, 2009). Our data provide evidence that LFA-1 disengagement and talin release from the IS are regulated by PKA.…”

Section: Discussionmentioning

confidence: 55%

TheBordetella pertussisadenylate cyclase toxin binds to T cells via LFA-1 and induces its disengagement from the immune synapse

Paccani¹,

Finetti²,

Davi³

et al. 2011

J Cell Biol

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The Bordetella pertussis adenylate cyclase toxin (CyaA) assists infection by potently suppressing the host immune response. Although CyaA effectively targets T lymphocytes, its putative receptor on these cells is unknown. Here, we show that CyaA binds to T cells via the  2 integrin LFA-1 in its active conformation. CyaA clusters with LFA-1 at the immune synapse (IS), from which it induces the premature disengagement of LFA-1 concomitant with the dissipation of talin, which tethers the integrin to the underlying actin cytoskeleton. The CyaA-induced redistribution of LFA-1 was cAMP-and protein kinase A (PKA)-dependent. These results not only identify LFA-1 as a CyaA receptor on T cells but unveil a novel mechanism of immunosuppression whereby the toxin parasitizes its interaction with LFA-1 to inhibit signaling at the IS through the local production of cAMP. The data also provide novel insights into the role of cAMP/PKA signaling in controlling the dynamics of the IS.

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Integrin signalling at a glance

Cited by 779 publications

References 57 publications

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

TheBordetella pertussisadenylate cyclase toxin binds to T cells via LFA-1 and induces its disengagement from the immune synapse

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