Sonic hedgehog (SHH) pathway. Patched 1 homolog (PTCH1) is activated either by binding of SHH ligand from a signaling cell or by intrinsic mutation, leading to relocalization of Smoothened (SMO) from the cell membrane. This activation results in signaling through Costal, COS, and suppressor of fused homolog (SuFu) and subsequent activation of GLI 1/2 transcription factors. Activated GLI transcription factors, which translocate to the nucleus, upregulate some genes—including cyclin-dependent kinases D and E (cyclin D and E); hedgehog-interacting protein (HIP), insulin-like growth factor binding protein-2 (IGFBP-2) and other IGFBPs, hairy and enhancer of split 1 (Hes1), sclerosin domain-containing 1 (Sostdc), phosphatidic acid phosphatase type 2B (Ppap2b), and bone morphogenic protein (BMP)—and downregulate others, including BMP and activin membrane-bound inhibitor (Bambi) and secreted frizzle-related protein 1–2 (Sfrp1-2). Upregulation of IGFBP-2 presumably results in an increase in IGFBP-2 expression in K14+ cells and in secretion of IGFBP-2 into the extracellular space around K14+ cells.
