Figure 1
From: Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
Janus kinase 2 (JAK2)/signal transducer and activation of transcription (STAT) and hedgehog (Hh) signaling pathways in normal development (A) and mechanisms of Hh signaling in cancer (B). (A) JAK/STAT signaling: the JAK2/STAT signaling pathway is activated upon binding of a cytokine to its receptor, causing phosphorylation and activation of JAK2, which then recruits and phosphorylates STATs. STATs dimerize, translocate to the nucleus, and activate target gene transcription. Hh signaling: in the absence of Hh ligand, patched (PTCH) inhibits smoothened (SMO). Glioma-associated oncogene homolog 1/2 (GLI1/2) transcription factors are sequestered in the cytoplasm by a repressor complex containing suppressor of fused (SUFU) and degraded. GLI3 is released from SUFU, processed into a repressor form (GLI3R), and translocates to the nucleus to inhibit transcription of Hh pathway target genes. Hh signaling is activated upon binding of Hh to PTCH. PTCH-mediated inhibition of SMO is relieved, and SMO activates release of GLIs from the SUFU complex. Activated GLIs (GLIA) then translocate to the nucleus to regulate target gene transcription. (B) Several mechanisms of Hh pathway activation in cancer have been proposed, including ligand independent (mutation driven) and ligand dependent (autocrine or paracrine) signaling. During autocrine signaling, Hh ligands produced in the tumor activate Hh signaling in the same tumor cells. Paracrine signaling can involve tumor-to-stroma signaling or stroma-to-tumor signaling (reverse paracrine). During tumor-to-stroma signaling, Hh ligands produced in the tumor activate Hh signaling in surrounding stromal cells, which release growth hormones that in turn feed tumor growth. In the reverse model (stroma-to-tumor), which has been observed in hematologic malignancies (lymphoma, myeloid neoplasms, and multiple myeloma), Hh ligands produced in stromal cells activate Hh signaling in the tumor. BCL2, B-cell CLL/lymphoma 2; BCL2L1, BCL2-like 1; BMP, bone morphogenetic protein; CCND1, cyclin D1; MCL1, myeloid cell leukemia sequence 1; PIM1, pim-1 oncogene.