CommentaryRegulator of G-protein signaling (RGS) proteins in cancer biology
Graphical abstract
Introduction
Cancer is characterized by the uncontrolled growth of cells through increased proliferation and decreased apoptosis. Additionally, cancer cells can invade adjacent tissues and metastasize to non-adjacent organs and tissues. Uncontrolled growth, invasion, and metastasis are due to changes in cellular signaling pathways, and oncogenic transformation is often the direct result of mutations of the signaling molecules which constitute these pathways. In the past decade, G-protein coupled receptor (GPCR)-stimulated pathways have emerged as critical mediators of oncogenic signaling. GPCRs are a family of cell surface receptors which activate heterotrimeric G-proteins to transduce extracellular signals into the interior of a cell. Regulators of G-protein signaling (RGS) proteins are a highly diverse family of proteins containing an RGS domain which accelerates the deactivation of heterotrimeric G-proteins, thus modulating signaling initiated by GPCRs. There are over 20 mammalian RGS proteins ranging from small proteins comprised solely of an RGS domain to multi-domain proteins with functions in multiple signaling pathways. These additional domains serve to mediate interactions with other signaling proteins, allowing RGS proteins to serve as signaling scaffolds. This review examines recent studies focused on the involvement of RGS proteins in the initiation and progression of cancer.
Section snippets
G-protein signaling in cancer biology
G-protein coupled receptors (GPCRs) are known to mediate a wide variety of physiological processes, including sensory perception, immune responses, neurotransmission, and cardiovascular activity. Consequently, GPCRs are also linked to many disease states and serve as direct and indirect targets for roughly half of pharmaceuticals currently on the market [1]. GPCRs function to mediate ligand-dependent activation of heterotrimeric guanine nucleotide binding proteins (G-proteins). Heterotrimeric
RGS proteins regulate G-protein signaling
GPCRs and G-proteins mediate a wide variety of signals and their activity is finely tuned by multiple regulatory proteins. One critical regulatory point in the G-protein cycle is the deactivation of G-proteins by GTP hydrolysis which is enhanced by GTPase activating proteins (GAPs) (Fig. 1). A group of proteins which function as heterotrimeric G-protein GAPs were identified over a decade ago in yeast, worms, and mammals and termed Regulator of G-protein Signaling proteins. Each RGS protein
Changes in expression of RGS transcripts and proteins in oncogenesis
The transformation of normal cells into cancerous cells requires concerted changes in the expression of multiple genes. These genetic changes result in the activation of proto-oncogenes and the inactivation of tumor suppressor genes allowing unregulated cell growth. Many recent studies have attempted to identify proto-oncogenes and tumor suppressors using multiplex gene microarray technology to compare the genetic profiles of matched samples of cancerous and normal tissues. Multiple RGS
RGS protein function in cancer
In addition to correlative studies demonstrating that changes in RGS gene expression are linked to cancer, there have also been several studies demonstrating functions of RGS proteins in cancer.
Conclusions
In the past decade, GPCRs and their cognate ligands have been shown to play a significant role in the initiation and progression of cancer; consequently, it is likely that regulators of GPCRs are also important to the regulation of oncogenic pathways. In this review, we present evidence that the RGS family of proteins play a role in multiple types of cancer. The transcription of over a dozen RGS genes is altered during oncogenesis and mutations in RGS genes have been shown to confer a reduced
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