Cellular and Molecular Mechanisms of PEAK1-Mediated TGFbeta Signaling and Function

Transforming growth factor beta (TGFbeta) has well-established roles in regulating both normal physiological and pathophysiological processes. The multi-faceted effects of TGFbeta are commonly mediated by both canonical Smad2/3 signaling and a variety of non-canonical signaling pathways. While TGFbeta signaling is essential during embryogenesis and tissue homeostasis, its dysregulation can lead to aberrant fibrosis (scarring) and cancer progression. Thus, it is essential to gain a complete understanding of the cellular and molecular regulation of TGFbeta signaling. To this end, our long-term goal is to develop a comprehensive mechanistic model for the function of the novel tyrosine kinase PEAK1 as a regulator of TGFbeta biology. The overall objective of this proposal is to investigate the cellular and molecular mechanisms by which PEAK1 regulates non-canonical TGFbeta signaling and epithelial-mesenchymal transition (EMT) in the context of normal physiology and disease. The proposed work is an extension of our recently published and compelling preliminary data showing that (i) PEAK1 expression is increased by and required for TGFbeta-induced EMT and cell migration; (ii) PEAK1 causes TGFbeta to induce cell proliferation; (iii) PEAK1 cooperates with integrin beta 3 (ITGB3) activation and causes TGFbeta signaling to switch from Smad2/3-dependent to Src/Grb2/MAPK-dependent pathways; (iv) PEAK1 is required for TGFbeta-induced ZEB1 upregulation during EMT; (v) PEAK1 is required for TGFbeta-induced metastasis in vivo; and (vi) blockade of eIF5A hypusination downregulates PEAK1 protein and inhibits TGFbeta-induced EMT. The rationale for the proposed research is that improved mechanistic insight into PEAK1-mediated TGFbeta signaling may identify novel strategies for intervention in human disease.