Abstract
The Rho-family of small GTPases are biological molecular switches that are best known for their regulation of the actin cytoskeleton. Through their activation and stimulation of downstream effectors, the Rho-family control pathways involved in cellular morphology, which are commonly activated in cancer cell invasion and metastasis. While this makes them excellent potential therapeutic targets, a deeper understanding of the downstream signalling pathways they influence will be required for successful drug targeting. Signal transducers and activators of transcription (STATs) are a family of transcription factors that are hyper-activated in most cancer types and while STATs are widely understood to be activated by the JAK family of kinases, many additional activators have been discovered. A growing number of examples of Rho-family driven STAT activation, largely of the oncogenic family members, STAT3 and STAT5, are being identified. Cdc42, Rac1, RhoA, RhoC and RhoH have all been implicated in STAT activation, contributing to Rho GTPase-driven changes in cellular morphology that lead to cell proliferation, invasion and metastasis. This highlights the importance and therapeutic potential of the Rho-family as regulators of non-canonical activation of STAT signalling.
Highlights
The Ras superfamily of small GTPases comprises over 150 biological molecular switches
MINC1 did not block Signal transducers and activators of transcription (STATs) nuclear translocation in HEK293 SIE-Luc cells [28]. Overall these results have revealed that the relationship between MgcRacGAP, STAT activation and STAT nuclear movement is highly context and cell type dependent but could be crucial for mediating nuclear translocation of active STAT dimers to the nucleus
Examples discussed in this review include Cdc42, Rac1, RhoA, RhoC and RhoH activation of oncogenic STAT3, and in some cases STAT5, in a range of cancers including but not limited to: breast, bladder, gastric, cervical, myeloid, pancreatic, hepatocellular, head and neck, and colorectal cancer
Summary
The Ras superfamily of small GTPases comprises over 150 biological molecular switches. As with Cdc42, expression of constitutively active Rac1 mutants has been shown to increase expression from both STAT3 and STAT5A-driven luciferase reporters in a variety of cell lines including: Rat1, HeLa, Figure 3.
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