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IQGAP1, RAS/MAPK pathway and Cancer

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There were 9,365 new cases of brain cancer (4,650 in med and 4,715 in women) registered in 2010 in the UK, leading to 4,975 deaths 1. The brain cancer with the highest aggressive behaviour is the glioblastoma. Glioblastoma has a rapidly growth, invasiveness and recurrence aspect 2. The Celldex Therapeutics researchers have been developing a new treatment using a vaccine that targets a mutated molecule involved in the activation of signaling pathways that control the cell proliferation, migration and survival. This molecule is called EGFRvIII (epidermal growth factor receptor variant III) and is the most common mutation in EGFR in this condition 2. The RAS-MAPK pathway is related to glioblastoma and is crutial regulated by the IQGAP1 protein 3.

RAS-MAPK pathway transduces the signal from outside of the cell to the nucleus culminating in the expression of the target gene. It involves RAS, RAF (MAPKKK), MEK (MAPKK), ERK (MAPK) proteins which is likely to be activated by the interaction of EGF to its receptor EGFR. However, the activation of this MAP kinase cascade requires a scaffold protein, IQGAP1, which is capable of interacting to form a complex with them. Also IQGAP1 is part of the GTPase family that acts stimulating the GTPase activity of G proteins and switching off its activity by changing GTP to GDP.

EGF receptors are found attached to the cell surface, and they are associated with normal cell growth and oncogenesis. EGFRvIII has the ability to enhance the tumorigenicity behaviour of a cell, stimulating its proliferation and angiogenesis 2. The cell migration process requires a few steps, such as cell proliferation and angiogenesis. The interaction of IQGAP1 with EGFRvIII, vascular endothelial growth factor receptor 2 (VE...

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...inase interaction blockade selectively targets RAS-MAP kinase-driven tumors." Nature medicine 19.5 (2013): 626-630.

4. Montano, Nicola, et al. "Expression of EGFRvIII in glioblastoma: prognostic significance revisited." Neoplasia (New York, NY) 13.12 (2011): 1113.

5. Meyer, Rosana D., David B. Sacks, and Nader Rahimi. "IQGAP1-dependent signaling pathway regulates endothelial cell proliferation and angiogenesis."PLoS One 3.12 (2008): e3848.

6. Balenci, Laurent, et al. "IQGAP1 protein specifies amplifying cancer cells in glioblastoma multiforme." Cancer research 66.18 (2006): 9074-9082.

7. Ho, Yen-Dong, et al. "IQGAP1 integrates Ca2+/calmodulin and Cdc42 signaling." Journal of Biological Chemistry 274.1 (1999): 464-470.

8. Johnson, Michael, Manisha Sharma, and Beric R. Henderson. "IQGAP1 regulation and roles in cancer." Cellular signalling 21.10 (2009): 1471-1478.
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