Roles of Integrin α6β4 Glycosylation in Cancer

Abstract

Malignant transformation is accompanied with aberrant glycosylation of proteins. Such changes in glycan structure also occur in the integrins, which are a large family of cell surface receptors for the extracellular matrix and play key roles in tumor progression. There is now increasing evidence that glycosylation of integrins affects cellular signaling and interaction with the extracellular matrix, receptor tyrosine kinases, and galectins, thereby regulating cell adhesion, motility, growth, and survival. Integrin α6β4 is a receptor for laminin-332 and the increased expression level is correlated with malignant progression and poor survival in various types of cancers. Recent studies have revealed that integrin α6β4 plays central roles in tumorigenesis and the metastatic process. In this review, we summarize our current understanding of the molecular mechanisms of tumor progression driven by integrin α6β4 and also discuss the modification of glycans on integrin β4 subunit to address the important roles of glycan in integrin-mediated tumor progression.

Exosome-derived ENO1 regulates integrin α6β4 expression and promotes hepatocellular carcinoma growth and metastasis

“…Surprisingly, exosomederived ENO1 can also upregulate integrin α6β4 expression in recipient cells, which exhibit increased proliferative activity, migratory and invasive capacities, and EMT activation. Integrin α6β4 is a crucial protein complex involved in the spreading and metastasis of tumor cells 65,66 . Integrin α6β4 separates from hemidesmosome-like structures in tumors, and this separation not only causes tumor cells to lose polarity and detach from the basement membrane but also causes upregulation of free integrin α6β4, which functions in bidirectional signal transduction and can, in turn, activate the relevant signaling pathways to promote tumor growth and metastasis 67,68 .…”

Cell-matrix adhesion controls Golgi organization and function through Arf1 activation in anchorage-dependent cells

“…Changes in Golgi organization and function might contribute to how proteins and lipids are processed and delivered ( Bankaitis et al, 2012 ; Rodriguez-Boulan and Müsch, 2005 ), which could also affect anchorage-dependent signaling. Malignant transformation in cancer cells is accompanied by aberrant glycosylation of proteins, including integrins and cadherins ( Kariya et al, 2017 ; Varki et al, 2009 ). In many cancers, the Golgi is fragmented to drive this change ( Migita and Inoue, 2012 ; Petrosyan, 2015 ).…”

Interplay between Cell-Surface Receptors and Extracellular Matrix in Skin

“…Elevated and suprabasal expression of integrin α6β4 is seen in all stages of squamous cell carcinoma (SCC) progression and it has been reported that high suprabasal expression primes SCCs for early relapse [68,[70][71][72]. Multiple mechanisms and molecular pathways, including glycan modifications and modulation of the immune microenvironment, underlie integrin α6β4-mediated tumor progression and are extensively reviewed elsewhere [73].…”