Integrin alpha9beta1: Unique signaling pathways reveal diverse biological roles

Abstract

Integrins are transmembrane heterodimeric receptors responsible for transducing and modulating signals between the extracellular matrix and cytoskeleton, ultimately influencing cell functions such as adhesion and migration. Integrin alpha9beta1 is classified within a two member sub-family of integrins highlighted in part by its specialized role in cell migration. The importance of this role is demonstrated by its regulation of numerous biological functions including lymphatic valve morphogenesis, lymphangiogenesis, angiogenesis and hematopoietic homeostasis. Compared to other integrins the signaling mechanisms that transduce alpha9beta1-induced cell migration are not well described. We have recently shown that Src tyrosine kinase plays a key proximal role to control alpha9beta1 signaling. Specifically it activates inducible nitric oxide synthase (iNOS) and in turn nitric oxide (NO) production as a means to transduce cell migration. Furthermore, we have also described a role for FAK, Erk and Rac1 in alpha9beta1 signal transduction. Here we provide an over view of known integrin alpha9beta1 signaling pathways and highlight its roles in diverse biological conditions.

Figure 1

Signaling mechanisms of integrin α9β1. (A) Selective ligation of integrin α9β1 activates proximal tyrosine kinase Src. Src coordinates subsequent signaling pathways; first through activation of FAK, tyrosine phosphorylation of the adaptor protein p130Cas and ultimately co-ordinates activation of small GTPase rac1, which translocates to the cell membrane and causes lamellipodial protrusion; second, Src activates iNOS resulting in increased NO production, activation of cGMP and protein kinase G signaling cascades to enhance cell migration (as reported by Gupta et al.16). (B) Integrin α9β1 can regionally recruit SSAT, an enzyme involved in the catabolism of higher order polyamines spermidine and spermine, which are potent blockers of inward rectifier K⁺ (Kir) channels. SSAT (along with PAO, polyamine oxidase) facilitates localized enzymatic processing of spermidine and spermine in to the smaller polyamine, putrescine and thus relieving outward efflux of K⁺ to co-ordinate cell migration (as reported by deHart et al.37).

Figure 2

Integrin crosstalk with growth factors and their cognate receptors. Left: shows direct ligation of integrin α9β1 by growth factors such as VEGF-A, C, D and NGF triggering the necessary signaling pathways to transduce cell attachment and migration (reported by Vlahakis et al., and Staniszewska et al.15). Right: shows an alternative mechanism, whereby growth factor stimulation (with or without) integrin ligation can promote co-association of growth factor receptor with integrins, where they synergize their respective effects. Specifically integrin α9β1 associates with VEGF-R2 or GCSF-R following co-stimulation of the integrin and the growth factor receptors with VEGF-A or GCSF, respectively to co-ordinate signaling for cell migration, proliferation, angiogenesis and granulopoiesis (as reported by Vlahakis et al. and Chen et al.41).