Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase

Abstract

Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin α9β1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin α9β1 signals migration. We found for the first time that specific ligation of integrin α9β1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin α9β1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-α9β1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin α9 was crucial for integrin-α9β1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin α9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-α9β1-mediated cell migration.

Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase

“…Thus, the improved wound healing by this compound was likely a result of cells migrating into the wounded area. Other studies have also shown that NO increases cell migration, but it can also inhibit motility, depending on the type of cell, level and duration of NO exposure, and assay conditions [44][45][46][47][48][49][50][51].…”

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

“…Conversely, integrin signaling modifies NO production. Activation of integrin alpha9/beta1 stimulates iNOS, thereby increasing NO production [108]. Signaling through integrin and integrin-linked kinase has been shown to regulate the expression of iNOS [109].…”

“…Integrins are thought to regulate glial migration to, and contact with, target cells, thereby playing a critical role in positioning glial cells. Cooperation and crosstalk between NO and integrins have been investigated in platelets [105], neutrophils [106], and endothelial cells [108,109], but not in glial cells. Therefore, it is imperative that future studies are carried out in order to address how the interplay between NO and integrins impacts on glial cell functions and on the progression of pathological pain.…”

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis

“…4C, right), suggesting the possible involvement of FAK-independent pathways in regulation of cadherin-11 expression beyond a9 engagement. FAKindependent PI3K signaling triggered by a9 activation (15,16) might play an important role in increasing cadherin-11 expression in FLSs under inflammatory conditions (35).…”

“…FAK is one of the first signaling molecules activated upon integrin engagement through autophosphorylation at Tyr 397 and triggers outside-in integrin signaling (14). Src and PI3K act cooperatively with FAK in this pathway but also activate FAK-independent pathways (15,16). Among various integrins expressed in FLSs, a9 is unique in that it does not bind to abundant ECM proteins such as fibronectin, laminins, vitronectin, or collagens but functions as a receptor for tenascin-C (Tn-C) (17), protease-cleaved osteopontin (18), VEGF-C (19), and thrombospondin-1 (20).…”