Cancer cells are subject to autocrine receptor stimulation by endogenous growth factors, and this stimulation contributes to malignant transformation and cancer development. Oral carcinoma cells often show increased (EGFR). Clinical correlation and in vitro and in vivo studies strongly suggest that increased EGFR stimulation by TGF-alpha contributes to carcinogenesis. TGF-alpha is made as a transmembrane growth factor, which undergoes regulated ectodomain cleavage or """"""""shedding"""""""" to release soluble and diffusible TGF-alpha. Transgenic experiments suggest that this cleavage of transmembrane TGF-alpha is required for its ability to stimulate carcinoma development. TGF-alpha ectodomain shedding is mediated by TACE, a transmembrane metalloprotease, which was originally discovered for its ability to mediate TNF-alpha cleavage. The mechanisms that activate TACE and consequent TGF-alpha cleavage were unknown until recently We have recently shown that growth factors, which activate tyrosine kinase receptors, induce ectodomain shedding of TGF-alpha as well as TNF- alpha and L-selectin Growth factor-induced TGF-alpha ectodomain shedding is mediated through activation of the Erk MAP kinase pathway and does not require new protein synthesis. We have also shown that the cytoplasmic domain of TACE is phosphorylated in response to growth factor stimulation and that the cytoplasmic domain of TGF-alpha ectodomain cleavage. This proposal now builds on these findings and is aimed at characterizing the signaling mechanism(s) that lead to activation of TGF-alpha shedding and its role in oral carcinoma development. We have subdivided the proposal in four Aims.
In Aim 1, we propose to characterize the growth factor-induced phosphorylation of TACE and its role in TACE activation and ectodomain shedding.
In Aim 2, we propose two different approaches to identify, clone and characterize the kinase, which phosphorylates TACE and in this way activates TACE mediated shedding in response to growth factor stimulation.
In Aim 3, we propose to identify and functionally characterize proteins that interact with TACE and, in this way regulate TACE activation and ectodomain shedding. Finally, in Aim 4, we will evaluate the role of TGF-alpha and its ectodomain cleavage, as a result of TACE activation and ectodomain shedding. Finally, in Aim 4, we will evaluate the role of TGF-alpha and its ectodomain cleavage, as a result of TACE activation in carcinogenesis and tumor development of oral squamous carcinoma in vivo.
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