Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

Coon, Brian G.; Baeyens, Nicolas; Han, Joungho; Budatha, Madhusudhan; Ross, Tyler D; Fang, Jennifer S.; Yun, Sanguk; Thomas, Jeon-Leon; Schwartz, Martin A.

doi:10.1085/jgp.1454oia13

Cited by 17 publications

(21 citation statements)

References 57 publications

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“…VEGFR3 is a highly mechanoresponsive RTK (Planas-Paz et al, 2012;Baeyens et al, 2015;Coon et al, 2015;Choi et al, 2017a;Lorenz et al, 2018), and b1 integrin is critically required for full VEGFR3 activation (Wang et al, 2001;Galvagni et al, 2010;Planas-Paz et al, 2012). Surprisingly, we identified ILK and b1 integrin to have opposing roles in VEGFR3 signalling and lymphatic vascular growth.…”

Section: Discussionmentioning

confidence: 64%

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

et al. 2018

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Vascular endothelial growth factor receptor‐3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell‐specific depletion of integrin‐linked kinase (ILK) in mouse embryos hyper‐activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)‐specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and β1 integrin in vitro and in vivo, and endothelial cell‐specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and β1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with β1 integrin and thus ensures proper development of lymphatic vessels.

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Section: Discussionmentioning

confidence: 64%

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

et al. 2018

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“…Therefore, CDH11 and PDGFRβ may be interacting through their transmembrane domains, similar to the interaction between VE-cadherin (CDH5) and VEGFR2/3 that mediated the response of endothelial cells to fluid flow. 30 Alternatively, other molecules could act as a bridge to connect CDH11 and PDGFRβ. For example, the PDZ I domain of NHERF-2 (Na + /H + exchanger regulator) was shown to bind PDGFRβ, while the PDZ II domain was identified as a binding domain for the C terminus of β-catenin, 31 a partner of all cadherins.…”

Section: Discussionmentioning

confidence: 99%

Cadherin‐11 binds to PDGFRβ and enhances cell proliferation and tissue regeneration via the PDGFR‐AKT signaling axis

et al. 2020

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Intercellular adhesion through homotypic interaction between cadherins regulates multiple cellular processes including cytoskeletal organization, proliferation, and survival. In this paper, we provide evidence that cadherin‐11 (CDH11) binds to and promotes cell proliferation both in vitro and in vivo in synergy with the platelet‐derived growth factor receptor beta (PDGFRβ). Engagement of CDH11 increased the sensitivity of cells to PDGF‐BB by 10‐ to 100‐fold, resulting in rapid and sustained phosphorylation of AKT, ultimately promoting and cell proliferation and tissue regeneration. Indeed, wound healing experiments showed that healing was severely compromised in Cdh11−/− mice, as evidenced by significantly decreased proliferation, AKT phosphorylation, and extracellular matrix (ECM) synthesis of dermal cells. Our results shed light into understanding how intercellular adhesion can promote cell proliferation and may have implications for tissue regeneration and cancer progression.

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“…(28). However, this signaling pathway was shown to regulate arterial lumen and atherogenesis, not angiogenesis (27)(28)(29)(30). Direct evidence for cross-talk between VEGFR2 and mechanical signaling in angiogenesis has been reported by Mammoto et al (26).…”

Section: Discussionmentioning

confidence: 99%

Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4

et al. 2018

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VEGF signaling via VEGF receptor-2 (VEGFR2) is a major regulator of endothelial cell (EC) functions, including angiogenesis. Although most studies of angiogenesis focus on soluble VEGF signaling, mechanical signaling also plays a critical role. Here, we examined the consequence of disruption of mechanical signaling on soluble signaling pathways. Specifically, we observed that small interfering RNA (siRNA) knockdown of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), significantly reduced perinuclear (Golgi) VEGFR2 in human ECs with a concomitant increase in phosphorylation at Y1175 and membrane translocation. TRPV4 knockout (KO) ECs exhibited increased plasma membrane localization of phospho-VEGFR2 compared with normal ECs. The knockdown also increased phospho-VEGFR2 in whole cell lysates and membrane fractions compared with control siRNA-treated cells. siRNA knockdown of TRPV4 enhanced nuclear localization of mechanosensitive transcription factors, yes-associated protein/transcriptional coactivator with PDZ-binding motif via rho kinase, which were shown to increase VEGFR2 trafficking to the plasma membrane. Furthermore, TRPV4 deletion/knockdown enhanced VEGF-mediated migration in vitro and increased expression of VEGFR2 in vivo in the vasculature of TRPV4 KO tumors compared with wild-type tumors. Our results thus show that TRPV4 channels regulate VEGFR2 trafficking and activation to identify novel cross-talk between mechanical (TRPV4) and soluble (VEGF) signaling that controls EC migration and angiogenesis.-Kanugula, A. K., Adapala, R. K., Midha, P., Cappelli, H. C., Meszaros, J. G., Paruchuri, S., Chilian, W. M., Thodeti, C. K., Novel non-canonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4.

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Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

Cited by 17 publications

References 57 publications

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth

Cadherin‐11 binds to PDGFRβ and enhances cell proliferation and tissue regeneration via the PDGFR‐AKT signaling axis

Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4

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