TA205, an anti‐talin monoclonal antibody, inhibits integrin–talin interaction

Xing, Baodong; Thuppal, Shalini; Jedsadayanmata, Arom; Du, Xiaoping; Lam, Stephen

doi:10.1016/j.febslet.2006.02.077

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…For example, Lai et al [33] showed that high Talin-1 expression in tumor tissues resulted in a poor prognosis of oral squamous cell carcinoma in ex vivo, whereas knockdown of Talin-1 expression inhibited proliferation and invasion ability of oral squamous cell carcinoma cells. The data reported by Xing et al [34] revealed that injection of an anti-Talin-1 antibody or antisense RNA was able to destroy the stress fibers of cellulose cells and inhibit adhesion, extension, and migration of breast cancer cells. In PCa, Zhang et al [15] showed that Talin-1 was overexpressed in PCa tissue specimens and cell lines, whereas microRNA-124 (miR-124) and Talin-1 impaired cellular adhesion and motility through integrins and the focal adhesion kinase/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer

Xu¹,

Chen²,

Chen³

et al. 2016

Medicine

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Talin-1 functions to regulate cell–cell adhesion, and its altered expression was reported to be associated with human carcinogenesis.A total of 280 tissue specimens from prostate cancer (PCa) patients who underwent radical prostatectomy, 75 cases of benign prostatic hyperplasia (BPH) tissue, and 6 cases of normal prostate tissue specimens were collected for construction of tissue microarray and subsequently subjected to immunohistochemical staining of Talin-1 expression.Talin-1 expression was significantly higher in PCa than both normal and BPH tissues (P <0.001). Talin-1 expression in PCa tissues was associated with preoperative prostate-specific antigen (PSA) level, Gleason score, tumor stage, lymph node metastasis, positive surgical margin, extracapsular extension and seminal vesicle invasion (all P <0.05). Logistic regression analysis showed that Talin-1 and Gleason score were independent risk factors for lymph node metastasis of PCa (P <0.001). Receiver operating characteristic (ROC) curve indicated that Talin-1 expression (AUC = 0.766) had a better accuracy to predict PCa lymph node metastasis than Gleason score (AUC = 0.697), whereas their combination could further enhance the prediction accuracy (AUC = 0.803). Kaplan–Meier curve analysis showed that increased Talin-1 expression was associated with shortened biochemical-free survival of PCa patients after radical prostatectomy (P <0.001).These findings suggested that Talin-1 protein was significantly upregulated in PCa tissues compared with that of BPH tissue and Talin-1 expression was an independent predictor for lymph node metastasis and biochemical recurrence of PCa. Further study will investigate the underlying molecular mechanism and the role of Talin-1 in PCa.

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Section: Discussionmentioning

confidence: 99%

Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer

Xu¹,

Chen²,

Chen³

et al. 2016

Medicine

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“…The generally high specificity of the antibody-antigen recognition confers a potential distinct selectivity advantage to this approach over conventional catalytic targeting approcahes. The anti-talin FERM antibody TA205 disrupts actin stress fibers and focal adhesion when microinjected into fibroblasts125 through an allosteric inhibition of the talin FERM domain binding to integrin cytoplasmic domain126 validating that a FERM domain-targeted monoclonal antibody could be used to disrupt FERM-ligand interaction intracellularly. The monoclonal antibody 12A10 specifically targets the Pyk2 FERM domain and recognizes an epitope located on the β5C-α1C surface of the F3 module of the FERM domain that overlaps a site that plays a role in Pyk2 activity 103.…”

Section: Strategies For Pyk2 Inhibitionmentioning

confidence: 92%

Targeting Pyk2 for therapeutic intervention

Lipinski

Loftus

2009

Expert Opinion on Therapeutic Targets

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Importance of the field-The focal adhesion tyrosine kinases FAK and Pyk2 are uniquely situated to act as critical mediators for the activation of signaling pathways that regulate cell migration, proliferation, and survival. By coordinating adhesion and cytoskeletal dynamics with survival and growth signaling, FAK and Pyk2 represent molecular therapeutic targets in cancer as malignant cells often exhibit defects in these processes.Areas covered in this review-This review examines the structure and function of the focal adhesion kinase Pyk2 and intends to provide a rationale for the employ of modulating strategies that include both catalytic and extra-catalytic approaches that have been developed in the last 3-5 years.What the reader will gain-Targeting tyrosine kinases in oncology has focused on the ATP binding pocket as means to inhibit catalytic activity and down-regulate pathways involved in tumor invasion. This review will discuss the available catalytic inhibitors and compare them to the alternative approach of targeting protein-protein interactions that regulate kinase activity Take home message-Development of specific catalytic inhibitors of the focal adhesion kinases has improved but significant challenges remain. Thus, approaches that inhibit the effector function of Pyk2 by targeting regulatory modules can increase specificity and will be a welcome asset to the therapeutic arena.

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“…In addition, the large loop insert in the F1 subdomain is a feature of talins and kindlins, and has been shown to be important for integrin activation by both adaptors (Goult et al, 2010;Bouaouina et al, 2012). Because antibody interference of the talin-integrin association using an F1 loop-directed monoclonal antibody, Ta205 (Xing et al, 2006), suggested proximity of the F1 loop to the integrin-binding F3 subdomain in the talin head, we decided to further investigate the role of the talin F1 loop in kindlin-1-assisted integrin clustering by assaying a series of loop deletions. In addition, we created a model of a FERM-folded talin head domain, containing the F1 loop, to study the biological role of the F1 loop in silico (Fig.…”

Section: Talin F1 Loop Is Required For Integrin Activation and Clusteringmentioning

confidence: 99%

The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering

Kukkurainen

Azizi

Zhang

et al. 2020

Journal of Cell Science

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Integrin activation and clustering by talin are early steps of cell adhesion. Membrane-bound talin head domain and kindlin bind to the β integrin cytoplasmic tail, cooperating to activate the heterodimeric integrin, and the talin head domain induces integrin clustering in the presence of Mn2+. Here we show that kindlin-1 can replace Mn2+ to mediate β3 integrin clustering induced by the talin head, but not that induced by the F2–F3 fragment of talin. Integrin clustering mediated by kindlin-1 and the talin head was lost upon deletion of the flexible loop within the talin head F1 subdomain. Further mutagenesis identified hydrophobic and acidic motifs in the F1 loop responsible for β3 integrin clustering. Modeling, computational and cysteine crosslinking studies showed direct and catalytic interactions of the acidic F1 loop motif with the juxtamembrane domains of α- and β3-integrins, in order to activate the β3 integrin heterodimer, further detailing the mechanism by which the talin–kindlin complex activates and clusters integrins. Moreover, the F1 loop interaction with the β3 integrin tail required the newly identified compact FERM fold of the talin head, which positions the F1 loop next to the inner membrane clasp of the talin-bound integrin heterodimer.This article has an associated First Person interview with the first author of the paper.

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TA205, an anti‐talin monoclonal antibody, inhibits integrin–talin interaction

Cited by 7 publications

References 26 publications

Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer

Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer

Targeting Pyk2 for therapeutic intervention

The F1 loop of the talin head domain acts as a gatekeeper in integrin activation and clustering

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