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. Author manuscript; available in PMC: 2019 Jan 30.
Published in final edited form as: Nat Rev Cancer. 2012 Sep 21;12(10):671–684. doi: 10.1038/nrc3322

Figure 2 |. Signalling pathways regulating self-renewal and differentiation shared between stem cells and T lymphocytes.

Figure 2 |

Self-renewal and differentiation are tightly balanced by opposing signals received from cell surface receptors. Self-renewal is promoted by WNT ligand binding to Frizzled–low-density lipoprotein receptor related protein 5 (LRP5) or LRP6 complexes or by ligand engagement of receptor complexes signalling through signal transducer and activator of transcription 3 (STAT3), including receptors containing the GP130 subunit or the interleukin-21 (IL-21) receptor. Activation of these signalling pathways leads to the transcription of target genes that favour self-renewal and that withhold differentiation, including STAT3 and Kruppel-like factor (KLF) family members and inhibitor of DNA binding (ID) proteins. Conversely, pro-mitotic cytokines such as IL-2 and growth factors can drive cellular differentiation by triggering the PI3K–AKT–mTOR pathway, as well as the RAS–RAF–MAPK pathway. The pro-differentiating influence of the RAS–RAF–MAPK pathway can be counteracted by SMAD signalling that is induced by transforming growth factor-β (TGFβ) or bone morphogenetic protein (BMP) family members through the induction of dual specificity phosphatase 9 (DUSP9) and the E protein regulators, ID molecules. Finally, activation of the Hippo pathways through a poorly characterized ligand–receptor interaction causes inactivation of Yes-associated protein (YAP), resulting in enhanced cellular differentiation. Between these self-renewal and pro-differentiation pathways exists a significant amount of crosstalk such that the net influence of each pathway is finely balanced and tuned. The dashed arrows indicate translocation into the nucleus. APC, adenomatous polyposis coli; CK1α, casein kinase 1, alpha 1; eIF4E, eukaryotic translation initiation factor 4E; FOXO, forkhead box O; GSK3β, glycogen synthase 3β; JAK, janus kinase; LATS, large tumour suppressor; LIF, leukaemia inhibitory factor; MOB, MOB kinase activator 1; MST, mammalian sterile-20-like kinases; p70S6K, p70 ribosomal protein S6 kinase 1; SAV1, salvador homologue 1; SHP2, SH2 domain-containing protein tyrosine phosphatase-2; TCF, T cell factor; TEAD, TEA domain family member; TSC, tuberous sclerosis.