Roles for epithelial integrin α3β1 in regulation of the microenvironment during normal and pathological tissue remodeling

Abstract

Integrin receptors for the extracellular matrix activate intracellular signaling pathways that are critical for tissue development, homeostasis, and regeneration/repair, and their loss or dysregulation contributes to many developmental defects and tissue pathologies. This review will focus on tissue remodeling roles for integrin α3β1, a receptor for laminins found in the basement membranes (BMs) that underlie epithelial cell layers. As a paradigm, we will discuss literature that supports a role for α3β1 in promoting ability of epidermal keratinocytes to modify their tissue microenvironment during skin development, wound healing, or tumorigenesis. Preclinical and clinical studies have shown that this role depends largely on ability of α3β1 to govern the keratinocyte's repertoire of secreted proteins, or the "secretome," including 1) matrix proteins and proteases involved in matrix remodeling and 2) paracrine-acting growth factors/cytokines that stimulate other cells with important tissue remodeling functions (e.g., endothelial cells, fibroblasts, inflammatory cells). Moreover, α3β1 signaling controls gene expression that helps epithelial cells carry out these functions, including genes that encode secreted matrix proteins, proteases, growth factors, or cytokines. We will review what is known about α3β1-dependent gene regulation through both transcription and posttranscriptional mRNA stability. Regarding the latter, we will discuss examples of α3β1-dependent alternative splicing (AS) or alternative polyadenylation (APA) that prevents inclusion of cis-acting mRNA sequences that would otherwise target the transcript for degradation via nonsense-mediated decay or destabilizing AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR). Finally, we will discuss prospects and anticipated challenges of exploiting α3β1 as a clinical target for the treatment of cancer or wound healing.

Keywords: alternative polyadenylation; alternative splicing; integrin α3β1; secretome; tissue microenvironment.

Graphical abstract

Figure 1.

Several modes of integrin α3β1-dependent gene regulation. α3β1 binding to its extracellular matrix (ECM) ligands (e.g., laminin-332) or cell surface binding partners (e.g., tetraspanin CD151) activates signaling pathways that control gene expression through (1) transcriptional mechanisms or mechanisms of posttranscriptional mRNA processing such as (2) alternative splicing (AS) and (3) alternative polyadenylation (APA). As depicted, α3β1-dependent AS or APA may regulate mRNA stability by determining inclusion or exclusion of cis-acting elements that target the transcript to nonsense-mediated mRNA decay (NMD) or ARE-mediated mRNA decay. For example, loss of α3β1-dependent AS may lead to retention of an intron harboring a premature termination codon (PTC) that targets the mRNA for NMD. Similarly, loss of α3β1-dependent APA may lead to utilization of a downstream polyadenylation site that generates an extended 3′-untranslated region (3′-UTR) with AU-rich elements (AREs) that destabilize the mRNA. Transcriptomic profiling shows that α3β1-dependent AS or APA extends to many genes, some of which encode secreted factors that modulate the tissue microenvironment through paracrine cross talk to other cells or ECM remodeling. See text for discussion of specific examples and references. Created with BioRender.com.