Basement Membrane Regulates Fibronectin Organization Using Sliding Focal Adhesions Driven by a Contractile Winch

Abstract

Highlights d Basement membrane matrix molecules can rapidly induce robust fibronectin assembly d A contractile actomyosin winch drives focal adhesion sliding and matrix assembly d Integrin switching mediates focal adhesion dynamics and fibronectin matrix assembly

Platelets exploit fibrillar adhesions to assemble fibronectin matrix revealing new force-regulated thrombus remodeling mechanisms

“…An extensive Fn network at basement membranes is known to guide cell migration during development (Lu et al 2020;Duband and Thiery 1982). We thus hypothesize that the plateletdeposited Fn fibrils at basement membranes could serve an analogous role during tissue repair.…”

“…In platelets, αIIbβ3 and not α5β1 integrins are the sole drivers of Fn stretching and fibrillogenesis (Figure 3). Adhesion signaling of either α6β1 on laminin, α2β1 on Col4, or αIIbβ3 on Fn or fibrin is sufficient to drive αIIbβ3 to assemble Fn fibrils (Figures 1,2,6), in analogy to the pre-activation of α5β1 integrins by αvβ3 in fibroblasts Bharadwaj et al 2017), the initiation of α5β1-containing sliding fibrillar adhesions by α3β1 or α2β1 integrins on Matrigel (Lu et al 2020), and in accordance with previous observations (Olorundare et al 2001;Jaehyung Cho et al 2005;Mosher 2006b, 2006a;Jaehyung Cho and Mosher 2006). Adhesion signaling through αIIbβ3 is essential to develop full contractility (Figure 4), maximal stress fibers (Lickert et al 2018), as well as a 3D apical anchorage of Fn fibrils as seen in fibroblasts (Figure 1) and a similar mechanomolecular strain within fibrillar adhesions ( Figure 5).…”

“…Emerging fibrillar adhesions in fibroblasts contain talin, which binds to the NPxY motif of β−integrins as well as to actin, while over time, talin is being replaced to variable extents by tensin controlled by phosphorylation of the NPxY motif (Legate and Fassler 2009). Very recent evidence suggests the existence of an alternative class of fibrillar adhesions in nucleated cells formed on basement membrane proteins through a mechanism in which an early focal adhesion becomes a sliding fibrillar adhesion that deposits Fn fibrils directly onto the basement membrane (Lu et al 2020). Here we now show striking morphological similarities between the adhesions fibroblasts and platelets exploit to pull fibronectin fibers, whereby their morphology gave them their name "fibrillar adhesions".…”

“…At first glance surprising is also why many different ECM protein coatings support reduced Fn deposition on Fn or fibrin substrates to different degrees (Olorundare et al 2001), but it remained again unclear whether this reduction was due to reduced platelet-substrate adhesion or to reduced Fn fibrillogenesis. Even for fibroblasts, the molecular mechanism how their mechanobiology drives the formation of fibrillar adhesions (Geiger et al 2001) is still debated and refined (Lu et al 2020), and nothing is known about the molecular machinery that drives Fn fibrillogenesis in platelets.…”

<p>Role of αVβ3 in Prostate Cancer: Metastasis Initiator and Important Therapeutic Target</p>

“…This series of changes eventually led to cell shape changes via transmission to the next αVβ3 molecule. 16,17 Integrin αVβ3 not only directly interacts with ECM but also regulates MMP (especially MMP-2 and MMP-9) expression through the PI3K signaling pathway to hydrolyze collagen in the ECM. [18][19][20] When tumor cells permeate into microvascular or lymphatic vessels, αVβ3 recruits some proteins with affinity to protect cells from complement or immune cell attack.…”