MAGP2 controls Notch via interactions with RGD binding integrins: Identification of a novel ECM–integrin–Notch signaling axis

DeFord, Peter; Brown, K.; Richards, Rae Lee; King, Aric; Newburn, Kristin; Westover, Katherine; Albig, Allan R.

doi:10.1016/j.yexcr.2016.01.011

Cited by 31 publications

(32 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanistically, MAGP-2 mediated stimulation of Notch signaling was shown to involve direct binding between the MAGP-2 C-terminal domain, and the EGF-like domains of Notch1 and Jagged1 [31]. In addition, RGD→RGE mutation of the MAGP-2 integrin binding domain converted MAGP-2 from a suppressor to an activator of Notch signaling in endothelial cells suggesting that MAGP-2 may also regulate Notch via interactions with integrins [32]. This finding may help to explain the cell type dependent effects of MAGP-2 on Notch signaling previously observed [33] and suggests that cell type specific control of Notch may be dependent on several factors including integrin and Notch ligand expression profiles.…”

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

“…Subsequent work showed that EGFL7 control of Notch in endothelial and placental trophoblast cells was important for placenta development and that decreased EGFL7 expression may be linked to preeclampsia [41, 42]. In addition to controlling Notch via direct interaction with Notch receptors, recent work showed that RGD→RGE mutation of the EGFL7 integrin-binding domain enhanced Notch signaling in endothelial cells [32]. By regulating Notch via direct interactions with Notch receptors and via RGD integrin binding, EGFL7 demonstrates similarities with MAGP-2 and suggest that dual control of Notch by ECM molecules is a common theme.…”

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

See 1 more Smart Citation

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

Self Cite

View full text Add to dashboard Cite

The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

show abstract

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

Section: Direct Ecm-notch Interactions That Control Notch Signalingmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, we speculated that MFAP5 may activate NOTCH2 signaling pathway through alternative ways. According to previous studies, MFAP5 interacts with multiple membrane receptors in an RGD‐domain relied manner 34,47 . We further investigated the role of MFAP5 in ligand receptor binding activation of NOTCH2 signaling pathway.…”

Section: Resultsmentioning

confidence: 94%

CAFs‐derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling

et al. 2020

View full text Add to dashboard Cite

Cancer‐associated fibroblasts (CAFs) are an important component of the tumor microenvironment and contribute to tumor cell proliferation and metastasis. Microfibrillar‐associated protein 5 (MFAP5), a component of elastic microfibers and an oncogenic protein in several types of tumors, is secreted by CAFs. However, the role of MFAP5 in the bladder cancer remains unclear. Here, we report that MFAP5 is upregulated in bladder cancer and is associated with poor patient survival. Downregulation of MFAP5 in CAFs led to an impairment in proliferation and invasion of bladder cancer cells. Luciferase reporter assays and electrophoretic mobility shift assays (EMSA) showed QKI directly downregulates MFAP5 in CAFs. In addition, CAFs‐derived MFAP5 led to an activation of the NOTCH2/HEY1 signaling pathway through direct interaction with the NOTCH2 receptor, thereby stimulating the N2ICD release. RNA‐sequencing revealed that MFAP5‐mediated PI3K‐AKT signaling activated the DLL4/NOTCH2 pathway axis in bladder cancer. Moreover, downregulation of NOTCH2 by short hairpin RNA or the inactivating anti‐body NRR2Mab was able to reverse the adverse effects of MFAP5 stimulation in vitro and in vivo. Together, these results demonstrate CAFs‐derived MFAP5 promotes the bladder cancer proliferation and metastasis and provides new insight for targeting CAFs as novel diagnostic and therapeutic strategy.

show abstract

“…As a soluble factor, EGFL7 would be readily available for either direct interaction with Notch receptors or with lower affinity membrane associated proteins. This hypothesis is fairly well supported by the fact that EGFL7 can directly bind Notch receptors , can interact with the αvβ3 integrin through its—not conserved—RGD motif which is in close proximity to the putative DSL (Delta/Serrate/LAG‐2) domain required for Notch receptor–ligand interaction and that the human EGFL7 RGD domain is also needed to modulate Notch signaling .…”

Section: Discussionmentioning

confidence: 96%

MAGP‐1 and fibronectin control EGFL7 functions by driving its deposition into distinct endothelial extracellular matrix locations

et al. 2018

View full text Add to dashboard Cite

The extracellular matrix (ECM) is essential to provide mechanical support to tissues but is also a bioactive edifice which controls cell behavior. Cell signaling generated by ECM components through integrin‐mediated contacts, modulates cell biological activity. In addition, by sequestrating or releasing growth factors, the ECM is an active player of physiological and pathological processes such as vascular development. EGFL7 is mainly expressed during blood vessel development and is deposited in the ECM after secretion by endothelial cells. While EGFL7 is known to control various endothelial cell molecular mechanisms [i.e., the repression of endothelial‐derived lysyl oxidase (LOX) enzyme, the regulation of the Notch pathway, and the expression of leukocyte adhesion molecules and of RHOA by endothelial cells], it is not established whether EGFL7 functions when bound to the ECM. Here, we show that microfibrillar‐associated glycoprotein‐1 (MAGP‐1) and fibronectin drive the deposition of EGFL7 into both fibers and individual aggregates in endothelial ECM. Although EGFL7 does not need to be docked into the ECM to control endothelial adhesion molecule expression, the ECM accumulation of EGFL7 is required for its regulation of LOX activity and of HEY2 expression along the Notch pathway. The interaction of EGFL7 with MAGP‐1 is necessary for LOX activity repression by EGFL7 while it does not participate in the control of the Notch pathway by this protein. Altogether, this study highlights the roles played by EGFL7 in controlling various endothelial molecular mechanisms upon its localization and shows how the ECM can modulate its functions.

show abstract

MAGP2 controls Notch via interactions with RGD binding integrins: Identification of a novel ECM–integrin–Notch signaling axis

Cited by 31 publications

References 38 publications

Notch: A multi-functional integrating system of microenvironmental signals

Notch: A multi-functional integrating system of microenvironmental signals

CAFs‐derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling

MAGP‐1 and fibronectin control EGFL7 functions by driving its deposition into distinct endothelial extracellular matrix locations

Contact Info

Product

Resources

About