HH/GLI signaling in nontransformed hematologic cells. (A) In the absence of HH ligand, HH/GLI signaling is actively repressed by the formation of GLI repressor transcription factors (GLI2/3R). In its unliganded form, the HH receptor PTCH prevents the entry of the essential HH effector SMO into cilia-like structures. The absence of SMO allows phosphorylation of SUFU-bound GLI transcription factors (GLI2/3) via PKA, CK1, and GSK-3β kinases. Phosphorylated GLI2/3 is partially degraded by the proteasome, yielding C-terminally truncated GLI repressor proteins that translocate to the nucleus to repress target gene expression. (B) Autocrine or paracrine HH signaling is initiated by binding of the HH ligand to its receptor, PTCH, resulting in shuttling and activation of SMO. Activated SMO prevents proteasomal degradation of GLI2/3 and promotes the release of GLI from inhibitory SUFU, resulting in GLI2/3 activator forms (GLI2/3A) and subsequent induction of HH target genes, including GLI1, amplifying the GLI activator signal. In addition, GLI activation can occur in a SMO-independent manner via PI3K/AKT/mTOR (light green) and Ras/Raf/MEK/ERK (light blue) signaling, or in a more indirect manner via cofactors and DNA modifiers, including casein kinases (CSNK1, CSNK2), DYRK1, atypical PKC, SRF-MKL1, BRD4, S6K, and class-I histone deacetylases (gray).