Multiple Functions of the Integrin α6β4 in Epidermal Homeostasis and Tumorigenesis

Abstract

Since the discovery of the ␣6␤4 integrin in the late 1980s, our understanding of its role in providing stable adhesion of epithelial cells to basement membranes (BM) has significantly increased. ␣6␤4 plays a key role in the formation and stabilization of junctional adhesion complexes called hemidesmosomes (HDs) that are connected to the intermediate filament (IF) system, as well as in the regulation of a variety of signaling processes. However, it is not clear as yet whether ␣6␤4 participates in cell signaling by serving as a substrate for tyrosine kinases and as an adaptor for their associated signaling proteins or whether its role in cellular processes is passive, involving regulation of the assembly and disassembly of HDs. In this review, we will discuss the roles attributed to ␣6␤4 and the controversies in the field. HISTORY OF THE ␣6␤4 INTEGRINThe integrin ␣6␤4 was discovered in the late 1980s by two different groups and was called either ␣E␤4 or Ic-Ic binding protein (Ic-IcBP) (36, 85). The Ic subunit had previously been shown to form a complex with glycoprotein IIa on platelets (86), which was subsequently identified as the common ␤1 subunit of the integrin family (63). Since the Ic subunit was immunologically and biochemically different from the five integrin ␣ subunits known at that time, it was named ␣6 and the complex of ␣6 with ␤1 was called VLA-6 (30). Subsequently IcBP, which for an integrin subunit had the unusual size of approximately 200 kDa, was found to be identical to the ␤4 subunit of the ␣E␤4 complex (29). The discovery of the integrin ␣6␤4 demonstrated that a particular ␣ subunit can dimerize with more than one ␤ subunit, a property that was then thought to be unique for ␤ subunits. In further studies, the tumor antigens TSP-180 and A9 were found to be identical to ␣6␤4 (39, 93). Increased expression of ␣6␤4 and changes in its distribution were then correlated with increased aggressiveness of tumors and poor prognosis (15,97). At the same time, ␣6␤4 was also found to be a component of HDs (34,84,87). Although ␣6␤4, like ␣6␤1, can interact with different laminin isoforms, its preferred ligand in the epidermal BM is laminin-5 (4, 57, 71).Sequencing of ␤4 revealed that its large size is due to an unusually long cytoplasmic domain of over 1,000 amino acids (31,89). This domain contains two pairs of type III fibronectin (FNIII) domains, separated by a connecting segment (CS) (Fig. 1). A Na-Ca exchanger (CalX) motif precedes the first FNIII domain, but its function is still not clear (77). Importantly, ␣6␤4 was found to be associated with keratin IFs instead of with actin like other integrins (26, 84). The association with IFs is mediated by the hemidesmosomal components plectin and BP230 (27,58,70). The importance of ␤4 for adhesion to the BM became evident in ␤4 knockout mice that developed severe blistering of the skin (14, 92). This was in line with findings, just prior to these studies, that a mutation in the ␤4 gene (ITGB4) is responsible for the pyloric atresia associated with junctional ...

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

“…Regardless of the initiating events and the amount of time needed to progress to metastasis, it is becoming clear that there are genes in which expression seems critical for the generation of a metastatic cell, and that these genes fit into the previously proposed essential alterations and steps toward metastasis (37,38). Among these genes are those that are up-regulated in 3T3.mD52 cells, including Vav3 (29), the antiapoptosis gene CARD10 (39), and integrin-a3 and integrin-a6, two members of the integrin family involved in the inhibition of apoptosis, growth stimulation, adhesion, and metastasis (30)(31)(32). Several genes that may be important in preventing tumor formation and metastasis were downregulated in 3T3.mD52 cells, including caveolin (34), four members of the cadherin gene family (40), specifically cadherins 11 and 2 and protocadherins 7 and 18, as well as the antiangiogenesis gene thrombospondin 2 (35).…”

“…In addition to a 24-fold increase in mD52 expression, several genes involved in cancer progression and metastasis showed increased expression in 3T3.mD52 cells (Table 1). Up-regulated genes include the oncogenes Vav3 (29), Myc, and homologue U of Ras, as well as adhesion molecules integrin-a3, integrin-a6 (30)(31)(32), and lamanin-a5 (Lama5; ref. 33).…”

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

“…25 More in general, a6b4 is necessary for tumor cell invasion, cooperates with c-met in the transformation of rodent fibroblasts and is necessary to maintain the tumorigenic phenotype of carcinoma cells. 44 Thus, the ability of NaHS to inhibit the expression of a6b4 can be reasonably considered relevant in the control of keratinocyte growth and adhesion.…”

“…As a mechanistic explanation of these effects, we show at the molecular level that (i) H 2 S reduces the Raf/MAPK kinase/ ERK signaling pathway, and (ii) the reduced adhesion of sulfur-treated cells is associated to the down-regulation of the expression of b4, a2 and a6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. [23][24][25] MATERIALS AND METHODS Cell Cultures Normal skin-derived immortalized human keratinocytes, clone NCTC 2544, were obtained from the American Tissue Culture Collection and cultured in EMEM medium (Euroclone, West York, UK) containing 10% fetal calf serum, penicillin (100 U/ml), streptomycin (100 mg/ml), and L-glutamine (2 mM). Cells were passaged two or three times weekly at ratios between 1:5 and 1:10.…”

Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

“…Integrins play an important role in the regulation of cell growth, and alterations in integrin expression have, not surprisingly, been associated with tumor growth as well. 37,38 Increased expression of integrin a6 has been related to the progression and metastasis of several epithelial cancers, where especially the integrin heterodimer a6b4 seems to be important, 39,40 although a6b1 may play some role as well. 41,42 Regarding our finding of the c-Jun-and transformation-dependent regulation of integrin a6, it is interesting to note that human integrin a6 gene has been shown to have a putative AP-1/CREB recognizing enhancer element.…”