scholarly journals Syndecans and Their Synstatins: Targeting an Organizer of Receptor Tyrosine Kinase Signaling at the Cell-Matrix Interface

2021 ◽  
Vol 11 ◽  
Author(s):  
Alan C. Rapraeger

Receptor tyrosine kinases (RTKs) and integrin matrix receptors have well-established roles in tumor cell proliferation, invasion and survival, often functioning in a coordinated fashion at sites of cell-matrix adhesion. Central to this coordination are syndecans, another class of matrix receptor, that organize RTKs and integrins into functional units, relying on docking motifs in the syndecan extracellular domains to capture and localize RTKs (e.g., EGFR, IGF-1R, VEGFR2, HER2) and integrins (e.g., αvβ3, αvβ5, α4β1, α3β1, α6β4) to sites of adhesion. Peptide mimetics of the docking motifs in the syndecans, called “synstatins”, prevent assembly of these receptor complexes, block their signaling activities and are highly effective against tumor cell invasion and survival and angiogenesis. This review describes our current understanding of these four syndecan-coupled mechanisms and their inhibitory synstatins (SSTNIGF1R, SSTNVEGFR2, SSTNVLA-4, SSTNEGFR and SSTNHER2).

2019 ◽  
Vol 30 (3) ◽  
pp. 346-356 ◽  
Author(s):  
Xi Wen ◽  
Xuehua Xu ◽  
Wenxiang Sun ◽  
Keqiang Chen ◽  
Miao Pan ◽  
...  

A dogma of innate immunity is that neutrophils use G-protein–coupled receptors (GPCRs) for chemoattractant to chase bacteria through chemotaxis and then use phagocytic receptors coupled with tyrosine kinases to destroy opsonized bacteria via phagocytosis. Our current work showed that G-protein–coupled formyl peptide receptors (FPRs) directly mediate neutrophil phagocytosis. Mouse neutrophils lacking formyl peptide receptors (Fpr1/2–/–) are defective in the phagocytosis of Escherichia coli and the chemoattractant N-formyl-Met-Leu-Phe (fMLP)-coated beads. fMLP immobilized onto the surface of a bead interacts with FPRs, which trigger a Ca2+response and induce actin polymerization to form a phagocytic cup for engulfment of the bead. This chemoattractant GPCR/Gi signaling works independently of phagocytic receptor/tyrosine kinase signaling to promote phagocytosis. Thus, in addition to phagocytic receptor-mediated phagocytosis, neutrophils also utilize the chemoattractant GPCR/Gi signaling to mediate phagocytosis to fight against invading bacteria.


2020 ◽  
Vol 295 (52) ◽  
pp. 18494-18507
Author(s):  
Kelly Karl ◽  
Michael D. Paul ◽  
Elena B. Pasquale ◽  
Kalina Hristova

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.


2013 ◽  
Vol 14 (9) ◽  
pp. 853-859 ◽  
Author(s):  
Katharine D Grugan ◽  
Maria E Vega ◽  
Gabrielle S Wong ◽  
J Alan Diehl ◽  
Adam J Bass ◽  
...  

Cancer ◽  
2010 ◽  
Vol 117 (4) ◽  
pp. 734-743 ◽  
Author(s):  
Xianzhou Song ◽  
Hua Wang ◽  
Craig D. Logsdon ◽  
Asif Rashid ◽  
Jason B. Fleming ◽  
...  

2015 ◽  
Vol 33 (5) ◽  
pp. 2495-2503 ◽  
Author(s):  
WENJUAN WU ◽  
XIZHI ZHANG ◽  
HAONAN QIN ◽  
WANXIN PENG ◽  
QINGYU XUE ◽  
...  

2021 ◽  
Author(s):  
Hongjiang Si ◽  
Na Zhao ◽  
Andrea Pedroza ◽  
Chad J. Creighton ◽  
Kevin Roarty

Cancer deaths largely result from metastasis, the spread of cancer from the primary tumor to distant organs. Initial steps of metastasis require that tumor cells invade into the surrounding tissue and gain access to blood or lymphatic vessels. Such invasion is reliant on a balance of cell-cell and cell-matrix cues within the microenvironment of the tumor, yet factors regulating such interactions for invading tumor cells remain elusive in the context of cancer. We demonstrate that the noncanonical Wnt receptor, Ror2, in mammary tumor models of Tripe Negative Breast Cancer, regulates the composition and remodeling of the tumor stroma, where Ror2-depletion prompts directional tumor cell invasion and coordinated ECM production at the leading edge of tumor cell movement. By RNA sequencing, we discovered that tumor organoids specifically harbor actin cytoskeleton, cell adhesion, and collagen cross-linking gene expression programs when Wnt/Ror2 signaling is impaired. Interestingly, Ror2 depletion resulted in the downregulation of E-cadherin in tumor organoids, particularly at invading tumor cell protrusions within the surrounding ECM. Spatially, we identified the upregulation and redistribution of integrin receptors, particularly integrin-α5 in Ror2-deficient tumor organoids, accompanied by the simultaneous production of a provisional Fibronectin matrix, a requisite component of the ECM, ligand for integrin α5, and mediator of collagen assembly and organization. Along with altered ECM architecture, Ror2 loss reshaped the topology of integrin and FAK activation within primary tumors, suggesting an important physiological function for Ror2 in shaping both signaling and ECM architecture during tumor progression. Blocking either integrin or FAK, a downstream mediator of integrin-mediated signal transduction, abrogated the enhanced migration observed upon Ror2 loss. These results suggest that Ror2 status within a tumor can significantly impact adhesive vs. migratory states in breast cancer and provide a novel mechanism where Wnt/Ror2 shapes not only tumor cell composition, but also reciprocal cell-ECM interactions prompting directional and collaborative tumor cell transit during cancer progression.


2001 ◽  
Vol 114 (12) ◽  
pp. 2279-2289 ◽  
Author(s):  
Tova Volberg ◽  
Lewis Romer ◽  
Eli Zamir ◽  
Benjamin Geiger

Activation of tyrosine kinases during integrin-mediated cell-matrix adhesion is involved both in the regulation of focal contact assembly and in the initiation of signaling processes at the cell-matrix adhesive interface. In order to determine the role of pp60c-src and related kinases in these processes, we have compared the dynamic reorganization of phosphotyrosine, vinculin, focal adhesion kinase and tensin in cells with altered expression of Src-family kinases. Both null cells for pp60c-src and triple knockout cells for pp60c-src, pp59fyn, and pp62c-yes exhibited decreased phosphotyrosine levels in focal contacts when compared with wild-type cells. pp60c-src-null cells also exhibited faster assembly of cell-matrix adhesions and a more exuberant recruitment of FAK to these sites. Tensin, which normally segregates into fibrillar adhesions was localized in large focal contacts in the two mutant cell lines, suggesting involvement of pp60c-src in the segregation of focal contacts and fibrillar adhesions. Moreover, treatment of wild-type cells with tyrphostin AG1007, which inhibits both pp60c-src and FAK activity, induced accumulation of tensin in peripheral focal adhesions. These findings demonstrate that Src family kinases, and pp60c-src in particular, have a central role in regulating protein dynamics at cell-matrix interfaces, both during early stages of interaction and in mature focal contacts.


2015 ◽  
Vol 26 (21) ◽  
pp. 3867-3878 ◽  
Author(s):  
Shannon K. Hughes ◽  
Madeleine J. Oudin ◽  
Jenny Tadros ◽  
Jason Neil ◽  
Amanda Del Rosario ◽  
...  

During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express MenaINV, which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5′ inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to the EGFR. When MenaINV is expressed, PTP1B recruitment to the EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor–induced signaling. Disruption of this attenuation by MenaINV sensitizes tumor cells to low–growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes.


Sign in / Sign up

Export Citation Format

Share Document