Ligation of β4 integrins activates PKB/Akt and ERK1/2 by distinct pathways—relevance of the keratin filament

Department of Dermatology and Venerology, University of Frankfurt Medical School, D-60590 Frankfurt/Main, Germany.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2010; 1803(8):940-50. DOI: 10.1016/j.bbamcr.2010.03.009
Source: PubMed


In normal epithelial cells hemidesmosomes mediate stable adhesion to the underlying basement membrane. In carcinoma cells a functional and spatial dissociation of the hemidesmosomal complex is observed stimulating the hypothesis that the beta4 integrin may trigger essential signalling cascades determining cell fate. In the present study we dissected the signalling pathways giving rise to PKB/Akt and ERK1/2 activation in response to beta4 ligation by 3E1. It was found that the activation of PKB/Akt is sensitive towards alterations of the keratin filament as demonstrated by using KEB-7 cells that carry a keratin mutation typical for epidermolysis bullosa simplex. Similar results were achieved by chemically induced keratin aggregations. Of note, the signalling to ERK1/2 was not affected. ERK1/2 activation utilizes an EGF-R transactivation mechanism as shown by dominant-negative expression experiments and also by treatment with a specific inhibitor (AG1478). Downstream from the EGF-R the activation of ERK1/2 takes the prototypical signalling cascade via Shc, Ras and Raf-1 as demonstrated by dominant-negative expression experiments. Taken together our data define a new model of beta4-dependent PKB/Akt and ERK1/2 activation demonstrating the keratin filament as a structure necessary in signal transmission.

Download full-text


Available from: August Bernd
  • Source
    • "Studies on dystonin-null mice have shown that detachment of keratin cytoskeleton from hemidesmosomes (4 integrin) reduces the ability of epidermal cells to exhibit migratory behaviour (Guo et al., 1995). Recently, it has also been demonstrated that alterations in keratin filaments, such as in epidermolysis bullosa simplex (EBS) or upon chemically induced aggregation, result in changes in 4-integrin-mediated signalling (Kippenberger et al., 2010). Here, we observed reduction in both total and cell surface levels of 4 integrin upon K8 knockdown (Fig. 4A–C). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression and invasion in squamous cell carcinomas (SCCs). To understand the molecular basis by which K8 promotes neoplastic progression in oral SCC (OSCC), K8 expression was inhibited in AW13516 cells. The K8-knockdown clones showed a significant reduction in tumorigenic potential, which was accompanied by a reduction in cell motility, cell invasion, decreased fascin levels, alterations in the organization of the actin cytoskeleton and changes in cell shape. Furthermore, K8 knockdown led to a decrease in α6β4 integrin levels and α6β4-integrin-dependent signalling events, which have been reported to play an important role in neoplastic progression in epithelial tissues. Therefore, modulation of α6β4 integrin signalling might be one of the mechanisms by which K8 and K18 promote malignant transformation and/or progression in OSCCs.
    Full-text · Article · Jun 2011 · Journal of Cell Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: The main function of the human sebaceous gland is sebum excretion. Increased sebum levels combined with follicular hyperkeratinization are a prerequisite of acne vulgaris. As peroxisome proliferator-activated receptors (PPARs) are known to control lipid metabolism in several human tissues they have been considered to be involved in the pathogenesis of acne vulgaris. To investigate the effect of activators of PPAR-α (WY14643), PPAR-γ (rosiglitazone) and PPAR-δ (L-165.041) on basal and staurosporine-induced apoptosis in the human sebocyte cell line SZ95 in vitro. After defining the basal effects of PPAR activators on membrane integrity (lactate dehydrogenase release) and DNA synthesis (5-bromodeoxyuridine incorporation), apoptosis was determined by the release of histone-associated DNA fragments. The underlying signalling events were detected by Western blotting and the use of specific inhibitors against p44/42 and protein kinase B (PKB)/Akt. PPAR activators of all three subsets offer antiapoptotic effects, with L-165.041 being the most potent. This compound induced the activation of PKB/Akt and p44/42, two kinases involved in antiapoptosis and proliferation, respectively. An inhibition of these kinases by specific inhibitors reversed the suppression of histone-associated DNA fragments by L-165.041, indicating that these signalling pathways participate in the observed antiapoptotic effect. The present data suggest that activators of PPAR, in particular of the δ subset, might have beneficial effects on acne vulgaris by inhibiting the release of lipids in the context of sebocyte apoptosis.
    No preview · Article · Jan 2011 · British Journal of Dermatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Akt/PKB kinases are central mediators of cell homeostasis. There are three highly homologous Akt isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ. Hyperactivation of Akt signaling is a key node in the progression of a variety of human cancer, by modulating tumor growth, chemoresistance and cancer cell migration, invasion and metastasis. It is now clear that, to understand the mechanisms on how Akt affects specific cancer cells, it is necessary to consider the relative importance of each of the three Akt isoforms in the altered cells. Akt1 is involved in tumor growth, cancer cell invasion and chemoresistance and is the predominant altered isoform found in various carcinomas. Akt2 is related to cancer cell invasion, metastasis and survival more than tumor induction. Most of the Akt2 alterations are observed in breast, ovarian, pancreatic and colorectal carcinomas. As Akt3 expression is limited to some tissues, its implication in tumor growth and resistance to drugs mostly occurs in melanomas, gliomas and some breast carcinomas. To explain how Akt isoforms can play different or even opposed roles, three mechanisms have been proposed: tissue-specificity expression/activation of Akt isoforms, distinct effect on same substrate as well as specific localization through the cyto-skeleton network. It is becoming clear that to develop an effective anticancer Akt inhibitor drug, it is necessary to target the specific Akt isoform which promotes the progression of the specific tumor.
    No preview · Article · Mar 2011 · Biomolecular concepts
Show more