Ras and RTK: PI3K Activation, PIP3 Formation, Signal Transduction, Cancer Creation

Ras mutations are implicated in over 30% of all cancers. Under normal conditions, Ras becomes active by binding to guanine triphosphate (GTP) to stimulate cell growth and division and other cell pathways. When Ras acquires specific mutations, it no longer binds the GTPase‐activating protein (GAP), which impairs the GAP GTPase activity, trapping Ras in its active state and leading to uncontrolled cell proliferation. The Ras family of G‐proteins play a role in recruitment of phosphatidylinositol‐3‐kinase (PI3K) to the membrane and stimulation of PIP3 lipid signaling. The Ras family consists of 3 major isoforms: H‐Ras, K‐Ras, and N‐Ras; all having similar functions in different pathways. The primary sequence of amino acids among the Ras isoforms is highly conserved with differences existing primarily between their C‐terminal tails. The Falke lab is studying the H‐Ras variant. H‐Ras, in its active GTP‐bound state, and receptor tyrosine kinase (RTK) synergistically recruit PI3K to the membrane and stimulate PI3K kinase activity. During recruitment to the lipid bilayer, PI3K binds its substrate lipid phosphatidylinositol‐4‐5‐bisphosphate (PIP2) and also binds adenosine triphosphate (ATP) and then phosphorylates PIP2, creating phosphatidylinositol (3,4,5)‐trisphosphate (PIP3). PIP3 then plays a central role in many cell growth and regulatory pathways by recruiting to the membrane many proteins that bind to its headgroup. Specific surface amino acid sidechains on Ras that bind to specific surface amino acid sidechains on the Ras‐binding domain (RBD) of PI3K during their interaction to assemble the fully active PI3K complex were modeled. Drugs that inhibit Ras or PI3K or their interaction may be effective in attacking cancer cell growth. Ultimately, understanding Ras and the mechanism of PI3K activation promotes understanding of a large subset of human cancers and facilitates the development of targeted treatments. The Longmont High School SMART (Students Modeling A Research Topic) Team modeled wild‐type H‐Ras and oncogenic mutants using 3D printing technology to investigate structure‐function relationships. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .