Abstract
Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes.
Highlights
The ability of tumour cells to escape their local environment and form distant metastases is a hallmark of cancer [1,2]
Given that expression of P-Rex1 appears to be a key determinant in formation of distant metastases in a number of models, including melanoma, breast and prostate cancer, we propose that in certain contexts PDGFRb and P-Rex1 may act as a novel, pro-invasive signalling module
Fibroblasts expressing a control vector or a line expressing a guanine nucleotide exchange factor (GEF)-dead mutant of P-Rex1incapable of catalysing GTP exchange (E56A, N238A – known as P-Rex1-GD) [9], exhibited no appreciable morphological changes when compared to the parental line (Figure 1B)
Summary
The ability of tumour cells to escape their local environment and form distant metastases is a hallmark of cancer [1,2]. Key players in this process are the RhoGTPase family of molecules, which have long been associated with the regulation of cancer cell morphology, motility and invasion [3]. P-Rex (PI(3,4,5)P3-dependent Rac exchanger 1) is a Racspecific member of the Dbl family of RhoGEFs – multidomain proteins which catalyse dissociation of GDP from inactive RhoGTPase molecules, and facilitate activation through loading with free intracellular GTP [6,7]. Since the oncogenic capacity of the Dbl gene product was isolated and shown to mediate GEF enzymatic activity for the RhoGTPase Cdc42 [10], numerous
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