Nuclear PI3K signaling in cell growth and tumorigenesis

Abstract

The PI3K/Akt signaling pathway is a major driving force in a variety of cellular functions. Dysregulation of this pathway has been implicated in many human diseases including cancer. While the activity of the cytoplasmic PI3K/Akt pathway has been extensively studied, the functions of these molecules and their effector proteins within the nucleus are poorly understood. Harboring key cellular processes such as DNA replication and repair as well as nascent messenger RNA transcription, the nucleus provides a unique compartmental environment for protein-protein and protein-DNA/RNA interactions required for cell survival, growth, and proliferation. Here we summarize recent advances made toward elucidating the nuclear PI3K/Akt signaling cascade and its key components within the nucleus as they pertain to cell growth and tumorigenesis. This review covers the spatial and temporal localization of the major nuclear kinases having PI3K activities and the counteracting phosphatases as well as the role of nuclear PI3K/Akt signaling in mRNA processing and exportation, DNA replication and repair, ribosome biogenesis, cell survival, and tumorigenesis.

Keywords: DNA damage; PI3K/Akt/mTOR; cell growth; cell survival; mRNA processing and export; nuclear signaling; ribosome biogenesis; tumorigenesis.

Figure 1

Nuclear distribution of the PI3K pathway. PI3K and many of its associated kinases (orange), phosphatases (blue), and phosphoinositides (yellow) reside natively in or translocate to the nucleus and nuclear sub-compartments, adding complexity to the established functional repertoire of the canonical PI3K pathway. The unique nuclear environment gives rise to non-canonical functions and molecular interactions not present in the cytoplasm. The uncertain role of nuclear PTEN in dephosphorylation of nuclear PI(3,4,5)P₃ is denoted by a dotted line.

Figure 2

Akt signaling in ribosome biogenesis. Ribosome biogenesis occurs largely in the nucleolus. The pre-initiation complex is composed, among other proteins, of RNA pol I, UBF, which binds the upstream control element (UCE) and the core element (CE), and SL1, which binds the CE (Knutson and Hahn, 2013). The products of RNA pol I and II and the ribosomal proteins conjoin to form the early 90S pre-ribosome which is processed to the pre-60S and pre-40S subunits (Grandi et al., ; Tschochner and Hurt, 2003). Akt activates rDNA transcription by stabilizing c-Myc, B23, and TIF-IA and through CK2 which also acts on TIF-IA. TIF-IA interacts directly with SL1 and RNA pol I, enhancing rDNA transcription (Miller et al., 2001). Through S6 kinase-1 (S6K-1), mTOR facilitates the interaction between UBF and SL1 (Hannan et al., 2003). mTOR can bind 5S rDNA promoters (Shor et al., 2010). The expression of rDNA transcribed by RNA pol I, II, and III is enhanced by c-Myc (Eilers and Eisenman, 2008) through direct rDNA binding and association with SL1, MAX (Amati et al., 1993), and TFIIIB (Gomez-Roman et al., 2003). Processing of the pre-rRNA transcripts involves Akt, c-Myc (Schlosser et al., 2003), mTORC1 (Iadevaia et al., 2012), and B23 (Maden, ; Savkur and Olson, 1998).

Figure 3

Molecular and biological functions of the nuclear PI3K pathway. The cell nucleus harbors a PI3K pathway that is functionally distinct from that of cytoplasm. The non-membranous localization of the nuclear phosphoinositides PI(4,5)P₂, PI(3,4)P₂, and PI(3,4,5)P₃ and their kinases as well as phosphatases form hubs for channeling divergent signaling to downstream molecular functions in the nucleus. These nuclear activities, in turn, guide cell survival and many physio-pathological processes including tumorigenesis.