Fig. 7

Phosphorylated CD133 regulates the PI3K-Akt and Src-FAK signaling pathways. a The Src-dependent phosphorylated tyrosine 828 in the CD133 IC3 binds to the PI3K regulatory subunit p85 via the SH2 domain in the latter, resulting in the translocation of the kinase to the plasma membrane and the phosphorylation of PIP₂ to yield PIP₃. Accumulation of the PIP₃ enables Akt to interact via its pleckstrin homology (PH) domain with the plasma membrane (PM), resulting in a conformational change in the Akt kinase domain, which allows the phosphorylation of a critical residue required for Akt kinase activity by the 3-phosphoinositide-dependent protein kinase 1 (PDK1). The mammalian TOR complex 2 (mTORC2) also phosphorylates Akt, promoting its kinase activity. It should be noted that PDK1 binding to PIP₃ is not essential for its activity, in contrast to the dependence of Akt on PIP₃. Then, the resulting activation of the PI3K/Akt pathway promotes self-renewal, cell survival and tumor formation. b The phosphorylated tyrosine 852 residue of CD133 directly interacts with Src and mediates its activation. The phosphorylated (p)-Src protein phosphorylates, and then forms a complex with, the FAK protein, triggering EMT-related events and cytoskeletal reorganization. This leads to increased cell motility and invasiveness, among other processes. Inhibition of Src activity by PP2, a known Src activity inhibitor, blocks the activation of FAK phosphorylation and cell migration induced by CD133 (not shown). Illustration in panel a is adapted from Ref [163], while in panel b is based on data from Ref [352]