RAKing in AKT: a tumor suppressor function for the intracellular tyrosine kinase FRK.

The Fyn related kinase FRK, originally called RAK, is a member of a small family of intracellular Src-related tyrosine kinases that includes PTK6 and Srms. These kinases share a conserved gene structure that is distinct from that of the Src family. Expression of FRK and PTK6 was originally identified in melanoma, breast cancer cells and normal intestinal epithelium, and both FRK and PTK6 have been implicated in the regulation of epithelial cell differentiation and apoptosis. Recently FRK was reported to phosphorylate the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10), a negative regulator of phosphatidylinositol 3 kinase (PI3K) signaling and AKT activation. FRK-mediated tyrosine phosphorylation of PTEN suppressed its association with NEDD4-1, an E3 ubiquitin ligase that may target it for polyubiquitination and proteosomal degradation. As a positive regulator of PTEN, FRK suppresses AKT signaling and inhibits breast cancer cell tumorgenicity in xenograft models. Both FRK and the related tyrosine kinase PTK6 appear to have multiple context-dependent functions, including the ability to regulate AKT. Although PTK6 negatively regulates AKT signaling in normal tissues in vivo, it may enhance AKT signaling in breast cancer cells. In contrast, FRK, which is expressed in the normal mammary gland but lost in some breast tumors, has tumor suppressor functions in mammary gland cells.