The α4β1/EMILIN1 interaction discloses a novel and unique integrin-ligand type of engagement

Capuano, Alessandra; Fogolari, Federico; Bucciotti, Francesco; Spessotto, Paola; Nicolosi, Pier Andrea; Mucignat, Maria Teresa; Cervi, Marta; Esposito, Gennaro; Colombatti, Alfonso; Doliana, Roberto

doi:10.1016/j.matbio.2017.10.001

Cited by 14 publications

(9 citation statements)

References 62 publications

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“…The study of the interactions between ligands and their biological targets greatly benefits from the availability of ligand-receptor crystallographic insights; since no X-ray analyses exist to date on the crystal structure of the α 4 β 1 receptor, or of the same receptor in complex with its small-molecule ligands, the design of a new class of cyclic Amp-based peptidomimetics required the generation and validation of a α 4 β 1 receptor model by molecular modelling studies [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

et al. 2021

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Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds.

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Section: Resultsmentioning

confidence: 99%

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

et al. 2021

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“…Scale bar: 50 μm; inset scale bar: 20 μm interaction with integrin (gC1q mutant). 25,35 Using the CLL-derived Mec-1 cells, strongly expressing CD49d (Figure S3B), 10 we observed a significant higher number of Mec-1 cells that adhered to normal (wild type) gC1q domain compared to gC1q mutant (mean values of adherent cells � s.e.m: 161 � 18 on gC1q domain vs. 61 � 13 on gC1q mutant; p = 0.001; Figure S3C). These data supported the idea that the interaction between EMILIN-1 and CLL cells through VLA-4 are mediated by the intact gC1q domain of EMILIN-1.…”

Section: Emilin-1 Promotes Vla-4-mediated Cll Cell Adhesion Via Its G...mentioning

confidence: 89%

Elastin MIcrofibriL INterfacer1 (EMILIN‐1) is an alternative prosurvival VLA‐4 ligand in chronic lymphocytic leukemia

Tissino

Pivetta

Capuano

et al. 2021

Hematological Oncology

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CD49d, the α4 chain of the VLA-4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell-microenvironment interactions mainly occurring via its ligands VCAM-1 and fibronectin. In the present study, we focused on EMILIN-1 (Elastin-MIcrofibriL-INterfacer-1), an alternative VLA-4 ligand whose role has been so far reported only in nonhematological settings, by investigating: i) the distribution of EMILIN-1 in CLL-involved tissues; ii) the capability of EMILIN-1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL; iii) the functional meaning of EMILIN-1 gC1q/VLA-4 interactions in CLL. EMILIN-1 is widely present in the CLL-involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot-like" and "mixed". The lack in CLL-BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN-1 and impairs EMILIN-1 function, suggests full functional EMILIN-1 in CLL independently of its expression pattern. Functionally, EMILIN-1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA-4, and releases pro-survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in-vitro-induced apoptosis. EMILIN-1/VLA-4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL.

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“…EMILIN1, the most notable member of the EMILIN/Multimerin family, was overexpressed in many organs, including blood vessels, lymphatic vessels, connective tissues, cardiovascular system and the central nervous system (Modica et al, 2017). The main functions of EMILIN1 include cell adhesion and migration in tumor growth (Capuano et al, 2018). Modica et al (2017) founded that EMILIN1 can silences the RAS-ERK pathway via alpha4beta1 integrin, decreasing tumor cell growth.…”

Section: Discussionmentioning

confidence: 99%

Expression patterns and the prognostic value of the EMILIN/Multimerin family members in low-grade glioma

Zhao¹,

Zhang²,

Yao³

et al. 2020

PeerJ

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Managing low-grade gliomas (LGG) remains a major medical challenge due to the infiltrating nature of the tumor and failure of surgical resection to eliminate the disease. EMILIN/Multimerins contain the gC1q signature, which is involved in many tumor processes. However, the expression and prognostic value of EMILIN/Multimerins in LGG remains unclear. This study used integrated bioinformatics analysis to investigate the expression pattern, prognostic value and function of EMILIN/Multimerins in patients with LGG. We analyzed the transcription levels and prognostic value EMILIN/Multimerins in LGG using the ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN databases. The mutation and co-expression rates of neighboring genes in EMILIN/Multimerins were studied using cBioPortal. TIMER and Metascape were used to reveal the potential function of EMILIN/Multimerins in LGG. According to our analysis, most EMILIN/Multimerins were overexpressed in LGG and shared a clear association with immune cells. GEPIA analysis confirmed that high levels of EMILIN/Multimerins, not including MMRN2, were associated with a poor prognosis in disease-free survival of patients with LGG. Additionally, we discovered that EMILIN/Multimerins may regulate LGG and we found a correlation between their expression patterns and distinct pathological grades. We found that EMILIN/Multimerins serve as possible prognostic biomarkers and high-priority therapeutic targets patients with LGG.

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The α4β1/EMILIN1 interaction discloses a novel and unique integrin-ligand type of engagement

Cited by 14 publications

References 62 publications

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin

Elastin MIcrofibriL INterfacer1 (EMILIN‐1) is an alternative prosurvival VLA‐4 ligand in chronic lymphocytic leukemia

Expression patterns and the prognostic value of the EMILIN/Multimerin family members in low-grade glioma

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