Figure 1.

KRAS major effectors and cellular functions. KRAS proteins are activated upon activation of an RTK-like EGFR. KRAS is a GTPase that functions as an on/off switch that alternates between an active GTP-bound and an inactive GDP-bound state, regulated by GAPs and GEFs, such as Sos1. This oncogene regulates several effector pathways, including the MAPK and PI3K/AKT pathways. GTP-bound KRAS leads to the activation of RAF proteins, resulting in the initiation of MAPK signaling. Subsequently, MEK is activated and, in turn, phosphorylates and activates ERK. Downstream of this, ERK can regulate numerous transcription factors, promoting cell cycle progression and influencing proliferation and apoptosis. Besides MAPK pathway, KRAS can interact with PI3K, whose activation leads to the phosphorylation of PIP2, resulting in PIP3. This second messenger is able to activate a large number of proteins containing a pleckstrin homology domain, including PDK1 and AKT, whose main downstream effector is mTOR. These proteins regulate cell cycle progression, cell survival, glucose metabolism, cell growth and proliferation. In addition to MAPK and PI3K/AKT pathways, KRAS can activate RALGDS, whose downstream effector is RAL GTPases, promoting cell cycle progression and survival. Furthermore, KRAS interacts with Tiam1, a Rho family GTPase, which is implicated in the development of RAS-driven tumors, growth transformation and promotion of cell survival. KRAS also binds to PLCε 44, a phospho-lipase C isoform responsible for KRAS mediated production of DAG, resulting in calcium release and activation of the PKC signaling cascade, involved in survival, proliferation, and calcium mobilization.