ErbB regulation of epidermal growth and differentiation
James T. Elder, MD PhD and Stefan Stoll, PhD
ErbB signaling in wound healing, non-melanoma skin cancer, prostate cancer, and psoriasis. The ErbB system is a family of four related receptor tyrosine kinases (ErbB1-4) which, when activated by specific ligands, trigger several signal transduction pathways leading to increased proliferation, survival, motility, and invasiveness (1). All of these responses are important aspects of wound healing, which appear to become "subverted" by epithelial cancers of the skin and many other organs. Dr. Elder's laboratory is particularly interested in basal cell carcinomas (BCC) of the skin. BCC is the most common form of cancer, accounting for one-third of all new US cancer diagnoses annually. His team found that BCC express ErbB1, ErbB2, and ErbB3, but not ErbB4. While expression levels of these receptors were comparable to normal skin, several findings indicated that ErbB signaling is hyperactive in the tumors: First, five different ErbB ligands were markedly and significantly overexpressed in bulk BCC tumors compared with normal skin. Second, tyrosine phosphorylation was markedly increased in BCC compared to normal or perilesional skin, and a specific increase in ErbB1 tyrosine phosphorylation was demonstrated in a subset of tumors. Third, a metastatic, recurrent BCC tumor markedly overexpressed ErbB1 and ErbB2, and displayed markedly increased tyrosine phosphorylation. Fourth, treatment of BCC organ cultures with specific inhibitors of ErbB receptor tyrosine kinase activity caused a marked decrease in matrix metalloproteinase elaboration. This work is currently being reviewed for publication.
The mechanisms by which ErbB signals translate into cancer phenotypes (migration, invasion, proliferation, and resistance to apoptosis) in keratinocytes remain incompletely defined. Drs. Stoll's and Elder's lab has identified amphiregulin as the key ligand, ErbB1 as the key receptor, and ERK as a key downstream mediator of an autocrine pathway of keratinocyte proliferation. We have shown that near-maximal ERK activation can be achieved at ligand concentrations barely able to increase tyrosine phosphorylation of ErbB1, and at which the vast majority of ErbB1 is not internalized. This work has been published recently (2).
Dr. Elder's team has also identified Src family kinases (SFKs) as an essential link between ErbB1 and ERK activation. Treatment of keratinocytes with SFK inhibitors produces a phenotype very similar to that induced by inhibition of ErbB or ERK: inhibition of proliferation, migration, and ERK phosphorylation. These phenotypes can be reversed by exogenous EGF, suggesting a site of action proximal to ErbB1. This suggestion was confirmed when Dr. Elder and his team found that SFK inhibitors markedly reduce the ability of keratinocytes to release amphiregulin into their environment. This work is currently being reviewed for publication.
Recently, Dr. Elder and Dr. Rajal Shah in the Department of Pathology have used immunohistochemical analysis of tissue microarrays to show that overexpression of ErbB1 is significantly correlated with progression of prostate cancers to androgen independence. This finding suggests that pharmacologic and monoclonal antibody inhibitors of ErbB1 may be valuable ways to specifically inhibit prostatic cancers which have "escaped" from control by anti-androgen treatment.
- Elder J.T., Kansra S., and Stoll S.W. Autocrine regulation of keratinocyte proliferation. J Clin Ligand Assay. 2004;27:137-142.
- *Kansra S., *Stoll S.W., Johnson J.L., Elder J.T. Autocrine ERK activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. Mol Biol Cell. 2004;15:4299-4309.
(*indicates equal contributions)
- Kansra S., Stoll S.W., Johnson J.L., Elder J.T. Src family kinase inhibitors block amphiregulin-mediated autocrine ErbB signaling in normal human keratinocytes. Mol Pharmacol. 2005;67:1145-1157.
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