Membrane-anchored wild-type and mutant Ras form dimers (or nanoclusters). Dimerization (or nanoclustering) is required for Raf's dimerization, activation, and Raf/MEK/ERK (MAPK) signaling (top part of the figure). By contrast, Ras dimerization (nanoclustering) is not required for PI3Kα activation, because PI3Kα essentially acts as a single unit (bottom part of the figure). Wild-type Ras activation of PI3Kα is helped by the phosphorylated C-terminal motif of RTK, which releases the autoinhibition of the p110 subunit by the p85 subunit. In the absence of RTK signaling, phosphorylated calmodulin helps oncogenic KRas. Because only KRas binds calmodulin, only KRas can fully activate PI3Kα/Akt signaling. Full activation of both MAPK and PI3Kα/Akt proliferative pathways by oncogenic KRas4B, but not by HRas or NRas, may help explain why the KRas4B isoform is especially highly populated in certain cancers. For details, see article by Nussinov and colleagues on page 593.