Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts

Abstract

The protein serine/threonine kinase Akt, also known as protein kinase B (PKB), is arguably the most important signalling nexus in the cell. Akt integrates a plethora of extracellular signals to generate diverse outcomes, including proliferation, motility, growth, glucose homeostasis, survival, and cell death. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is the second most frequently mutated pathway in cancer, after p53, and mutations in components of this pathway are found in around 70% of breast cancers. Thus, understanding how Akt relays input signals to downstream effectors is critically important for the design of therapeutic strategies to combat breast cancer. In this review, we will discuss the various signals upstream of Akt that impact on its activity, how Akt integrates these signals and modulates the activity of downstream targets to control mammary gland development, and how mutations in components of the pathway result in breast cancer.

Figure 1

Signalling from receptor tyrosine kinases to Akt is mediated by PI3kinase regulatory subunits and adaptor molecules that activate PI3K, which in turn converts PIP₂ to PIP₃. FOXO, Forkhead family of transcription factors; GSK3, glycogen synthase kinase 3; IGF 1/2, insulin-like growth factor 1/2; IL-6, interleukin-6; IRS, insulin receptor substrate; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa-B; P, phosphate; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP₂, phosphatidylinositol 4,5 diphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; RTK, receptor tyrosine kinase; S6K, S6 kinase.

Figure 2

Signals feeding into Akt and their relay to downstream target molecules and cellular processes. DR, death receptor; FOXO, Forkhead family of transcription factors; GSK3, glycogen synthase kinase 3; IGF 1/2, insulin-like growth factor 1/2; IKKβ/2, inhibitor of kappa-B kinase β/2; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa-B; P, phosphate; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP₂, phosphatidylinositol 4,5 diphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; S6K, S6 kinase; TSC1/2, tuberous sclerosis complex 1/2.

Figure 3

Therapeutic drugs that target various components of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; mTOR, mammalian target of rapamycin; VEGFR, vascular endothelial growth factor receptor.